mTOR inhibitors are a
class of drugs
A drug class is a set of medications and other compounds that have a similar chemical structures, the same mechanism of action (i.e. binding to the same biological target), a related mode of action, and/or are used to treat the same disease.
In ...
that inhibit the
mechanistic target of rapamycin
The mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the ''MTOR'' gene. ...
(mTOR), which is a
serine/threonine-specific protein kinase
A serine/threonine protein kinase () is a kinase enzyme, in particular a protein kinase, that phosphorylates the OH group of the amino-acid residues serine or threonine, which have similar side chains. At least 350 of the 500+ human protei ...
that belongs to the family of
phosphatidylinositol-3 kinase (PI3K) related kinases (PIKKs). mTOR regulates cellular metabolism, growth, and proliferation by forming and signaling through two
protein complexes
A protein complex or multiprotein complex is a group of two or more associated polypeptide chains. Protein complexes are distinct from multienzyme complexes, in which multiple catalytic domains are found in a single polypeptide chain.
Protein c ...
,
mTORC1
mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis.
mTOR Complex 1 (mTORC1) is compo ...
and
mTORC2. The most established mTOR inhibitors are so-called rapalogs (rapamycin and its analogs), which have shown tumor responses in clinical trials against various tumor types.
History
The discovery of mTOR was made a few decades ago while investigating the
mechanism of action
In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targe ...
of its
inhibitor
Inhibitor or inhibition may refer to:
In biology
* Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity
* Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotra ...
,
rapamycin
Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection, treat a rare lung disease called lymphangioleiomyomatosis, ...
.
Rapamycin was first discovered in 1975 in a soil sample from
Easter Island
Easter Island ( rap, Rapa Nui; es, Isla de Pascua) is an island and special territory of Chile in the southeastern Pacific Ocean, at the southeasternmost point of the Polynesian Triangle in Oceania. The island is most famous for its nearl ...
of
South Pacific, also known as Rapa Nui, from where its name is derived.
Rapamycin is a
macrolide
The Macrolides are a class of natural products that consist of a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered. Macrol ...
, produced by the
microorganism
A microorganism, or microbe,, ''mikros'', "small") and ''organism'' from the el, ὀργανισμός, ''organismós'', "organism"). It is usually written as a single word but is sometimes hyphenated (''micro-organism''), especially in olde ...
''
Streptomyces hygroscopicus
''Streptomyces hygroscopicus'' is a bacterial species in the genus '' Streptomyces''. It was first described by Hans Laurits Jensen in 1931.
Biochemistry
Cultures of different strains of ''S. hygroscopicus'' can be used to produce a number of ...
'' and showed
antifungal
An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as crypto ...
properties. Shortly after its discovery,
immunosuppressive
Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reacti ...
properties were detected, which later led to the establishment of rapamycin as an immunosuppressant. In the 1980s, rapamycin was also found to have anticancer activity although the exact mechanism of action remained unknown until many years later.
In the 1990s there was a dramatic change in this field due to studies on the mechanism of action of rapamycin and the identification of the drug target.
It was found that rapamycin inhibited
cellular proliferation
Cell growth refers to an increase in the total mass of a cell, including both cytoplasmic, nuclear and organelle volume. Cell growth occurs when the overall rate of cellular biosynthesis (production of biomolecules or anabolism) is greater than ...
and
cell cycle progression
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subse ...
. Research on mTOR inhibition has been a growing branch in science and has promising results.
Protein kinases and their inhibitors
![FKBP-sirolimus-mTOR complex 1FAP](https://upload.wikimedia.org/wikipedia/commons/8/85/FKBP-sirolimus-mTOR_complex_1FAP.png)
In general,
protein kinase
A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a fu ...
s are classified in two major categories based on their substrate specificity,
protein tyrosine kinases and
protein serine/threonine kinases.
Dual-specificity kinase
In biochemistry, a dual-specificity kinase () is a kinase that can act as both tyrosine kinase and Serine/threonine-specific protein kinase, serine/threonine kinase.
Mitogen-activated protein kinase kinase, MEKs, involved in Mitogen-activated prot ...
s are subclass of the tyrosine kinases.
mTOR is a kinase within the family of
phosphatidylinositol-3 kinase-related kinases (PIKKs),
which is a family of serine/threonine protein kinases, with a sequence similarity to the family of lipid kinases,
PI3Ks.
These kinases have different biological functions,
but are all large proteins with common domain structure.
![Domain structure of mTOR](https://upload.wikimedia.org/wikipedia/commons/a/a5/Domain_structure_of_mTOR.png)
PIKKs have four domains at the protein level, which distinguish them from other protein kinases. From the
N-terminus
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
to the
C-terminus
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
, these domains are named FRAP-ATM-TRAAP (FAT),
the kinase domain (KD), the PIKK-regulatory domain (PRD), and the FAT-C-terminal (FATC).
The FAT domain, consisting of four
α-helices
The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ear ...
, is N-terminal to KD, but that part is referred to as the FKBP12-rapamycin-binding (FRB) domain, which binds the FKBP12-rapamycin complex.
The FAT domain consists of repeats, referred to as
HEAT
In thermodynamics, heat is defined as the form of energy crossing the boundary of a thermodynamic system by virtue of a temperature difference across the boundary. A thermodynamic system does not ''contain'' heat. Nevertheless, the term is al ...
(
Huntingtin
Huntingtin (Htt) is the protein coded for in humans by the ''HTT'' gene, also known as the ''IT15'' ("interesting transcript 15") gene. Mutated ''HTT'' is the cause of Huntington's disease (HD), and has been investigated for this role and also for ...
,
Elongation factor 3, A subunit of
protein phosphatase 2A Protein phosphatase 2A may refer to:
* Protein phosphatase 2
Protein phosphatase 2 (PP2), also known as PP2A, is an enzyme that in humans is encoded by the ''PPP2CA'' gene. The PP2A heterotrimeric protein phosphatase is ubiquitously expressed, ...
and TOR1).
Specific protein activators regulate the PIKK kinases but binding of them to the kinase complex causes a conformational change that increases substrate access to the kinase domain.
Protein kinases have become popular drug targets.
They have been targeted for the discovery and design of
small molecule
Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs ar ...
inhibitors and
biologics
A biopharmaceutical, also known as a biological medical product, or biologic, is any pharmaceutical drug product manufactured in, extracted from, or semisynthesized from biological sources. Different from totally synthesized pharmaceuticals, th ...
as potential therapeutic agents. Small-molecule inhibitors of protein kinases generally prevent either
phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
of proteins
substrates or
autophosphorylation
Autophosphorylation is a type of post-translational modification of proteins. It is generally defined as the phosphorylation of the kinase by itself. In eukaryotes, this process occurs by the addition of a phosphate group to serine, threonine or ...
of the kinase itself.
mTOR signaling pathway
It appears that
growth factors
A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regu ...
,
amino acids
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
,
ATP, and
oxygen
Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as wel ...
levels regulate mTOR signaling. Several
downstream pathways that regulate cell-cycle progression,
translation
Translation is the communication of the Meaning (linguistic), meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The ...
,
initiation
Initiation is a rite of passage marking entrance or acceptance into a group or society. It could also be a formal admission to adulthood in a community or one of its formal components. In an extended sense, it can also signify a transformation ...
, transcriptional stress responses,
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
stability, and
survival of cells are signaling through mTOR.
![MTOR complexes](https://upload.wikimedia.org/wikipedia/commons/e/e0/MTOR_complexes.png)
The
serine/threonine kinase
A serine/threonine protein kinase () is a kinase enzyme, in particular a protein kinase, that phosphorylates the OH group of the amino-acid residues serine or threonine, which have similar side chains. At least 350 of the 500+ human protei ...
mTOR is a downstream effector of the
PI3K/AKT pathway, and forms two distinct
multiprotein complex
A protein complex or multiprotein complex is a group of two or more associated polypeptide chains. Protein complexes are distinct from multienzyme complexes, in which multiple catalytic domains are found in a single polypeptide chain.
Protein c ...
es,
mTORC1
mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis.
mTOR Complex 1 (mTORC1) is compo ...
and
mTORC2.
These two complexes have a separate network of protein partners,
feedback loops
Feedback occurs when outputs of a system are routed back as inputs as part of a chain of cause-and-effect that forms a circuit or loop. The system can then be said to ''feed back'' into itself. The notion of cause-and-effect has to be handled ...
,
substrates, and regulators.
mTORC1 consists of mTOR and two positive regulatory subunits,
raptor
Raptor or RAPTOR may refer to:
Animals
The word "raptor" refers to several groups of bird-like dinosaurs which primarily capture and subdue/kill prey with their talons.
* Raptor (bird) or bird of prey, a bird that primarily hunts and feeds on v ...
and mammalian LST8 (
mLST8
Target of rapamycin complex subunit LST8, also known as mammalian lethal with SEC13 protein 8 (mLST8) or TORC subunit LST8 or G protein beta subunit-like (GβL or Gable), is a protein that in humans is encoded by the ''MLST8'' (MTOR associated pro ...
), and two negative regulators, proline-rich
AKT
Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transc ...
substrate 40 (PRAS40) and DEPTOR.
mTORC2 consists of mTOR, mLST8,
mSin1, protor,
rictor
Rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR) is a protein that in humans is encoded by the ''RICTOR'' gene.
RICTOR and mTOR are components of a protein complex that integrates nutrient- and growth factor-derived si ...
, and DEPTOR.
mTORC1 is sensitive to rapamycin but mTORC2 is considered to be resistant and is generally insensitive to nutrients and energy signals. mTORC2 is activated by
growth factor
A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regu ...
s,
phosphorylates
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, whi ...
PKCα,
AKT
Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transc ...
and
paxillin
Paxillin is a protein that in humans is encoded by the ''PXN'' gene. Paxillin is expressed at focal adhesions of non-striated cells and at costameres of striated muscle cells, and it functions to adhere cells to the extracellular matrix. Mutation ...
, and regulates the activity of the small
GTPase
GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a pro ...
,
Rac
RAC or Rac may refer to:
Organizations
* Radio Amateurs of Canada
* RATCH-Australia Corporation, electricity generator
* Refugee Action Collective (Victoria), Melbourne, Australia
* Religious Action Center of Reform Judaism, US
* Rent-A-Center, ...
, and
Rho
Rho (uppercase Ρ, lowercase ρ or ; el, ρο or el, ρω, label=none) is the 17th letter of the Greek alphabet. In the system of Greek numerals it has a value of 100. It is derived from Phoenician letter res . Its uppercase form uses the sa ...
related to cell survival,
migration
Migration, migratory, or migrate may refer to: Human migration
* Human migration, physical movement by humans from one region to another
** International migration, when peoples cross state boundaries and stay in the host state for some minimum le ...
and regulation of the
actin cytoskeleton
Microfilaments, also called actin filaments, are protein filaments in the cytoplasm of eukaryotic cells that form part of the cytoskeleton. They are primarily composed of polymers of actin, but are modified by and interact with numerous other pr ...
.
The mTORC1 signaling cascade is activated by phosphorylated AKT and results in phosphorylation of
S6K1
Ribosomal protein S6 kinase beta-1 (S6K1), also known as p70S6 kinase (p70S6K, p70-S6K), is an enzyme (specifically, a protein kinase) that in humans is encoded by the ''RPS6KB1'' gene. It is a serine/threonine kinase that acts downstream of PIP3 ...
, and
4EBP1
Eukaryotic translation initiation factor 4E-binding protein 1 (also known as 4E-BP1) is a protein that in humans is encoded by the ''EIF4EBP1'' gene.
Function
This gene encodes one member of a family of translation repressor proteins. The prot ...
, which lead to
mRNA translation
In molecular biology and genetics, translation is the process in which ribosomes in the cytoplasm or endoplasmic reticulum synthesize proteins after the process of transcription of DNA to RNA in the cell's nucleus. The entire process ...
.
mTOR signaling pathway in human cancer
![MTOR signal pathway](https://upload.wikimedia.org/wikipedia/commons/3/3d/MTOR_signal_pathway.jpg)
Many human tumors occur because of dysregulation of mTOR signaling, and can confer higher susceptibility to inhibitors of mTOR.
Deregulations of multiple elements of the mTOR pathway, like PI3K
amplification/
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
,
PTEN loss of function,
AKT
Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transc ...
overexpression, and S6K1, 4EBP1, and
eIF4E
Eukaryotic translation initiation factor 4E, also known as eIF4E, is a protein that in humans is encoded by the ''EIF4E'' gene.
Structure and function
Most eukaryotic cellular mRNAs are blocked at their 5'-ends with the 7-methyl-guanosine fi ...
overexpression have been related to many types of cancers. Therefore, mTOR is an interesting
therapeutic target for treating multiple cancers, both the mTOR inhibitors themselves or in combination with inhibitors of other pathways.
Upstream, PI3K/AKT signalling is deregulated through a variety of mechanisms, including overexpression or activation of
growth factor receptor
A growth factor receptor is a receptor that binds to a growth factor. Growth factor receptors are the first stop in cells where the signaling cascade for cell differentiation and proliferation begins. Growth factors, which are ligands that bind to ...
s, such as
HER-2
Receptor tyrosine-protein kinase erbB-2 is a protein that in humans is encoded by the ''ERBB2'' gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently refer ...
(human epidermal growth factor receptor 2) and
IGFR (insulin-like growth factor receptor), mutations in
PI3K
Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
and mutations/amplifications of AKT.
Tumor suppressor phosphatase and tensin homologue deleted on
chromosome 10
Chromosome 10 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 10 spans about 133 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the tota ...
(PTEN) is a negative regulator of PI3K signaling. In many cancers the PTEN expression is decreased and may be downregulated through several mechanisms, including
mutations
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
,
loss of heterozygosity
Loss of heterozygosity (LOH) is a type of genetic abnormality in diploid organisms in which one copy of an entire gene and its surrounding chromosomal region are lost. Since diploid cells have two copies of their genes, one from each parent, a sing ...
,
methylation
In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...
, and protein instability.
Downstream, the mTOR effectors S6 kinase 1 (S6K1),
eukaryotic initiation factor 4E-binding protein 1 (4EBP1) and eukaryotic initiation factor 4E (eIF4E) are related to cellular transformation.
S6K1 is a key regulator of cell growth and also phosphorylates other important targets. Both eIF4E and S6K1 are included in
cellular transformation
In molecular biology and genetics, transformation is the genetic alteration of a cell resulting from the direct uptake and incorporation of exogenous genetic material from its surroundings through the cell membrane(s). For transformation to ta ...
and their overexpression has been linked to poor cancer prognosis.
Development of mTOR inhibitors
Since the discovery of mTOR, much research has been done on the subject, using rapamycin and rapalogs to understand its biological functions.
The clinical results from targeting this pathway were not as straight forward as thought at first. Those results have changed the course of clinical research in this field.
Initially, rapamycin was developed as an antifungal drug against ''
Candida albicans
''Candida albicans'' is an opportunistic pathogenic yeast that is a common member of the human gut flora. It can also survive outside the human body. It is detected in the gastrointestinal tract and mouth in 40–60% of healthy adults. It is us ...
'', ''
Aspergillus fumigatus
''Aspergillus fumigatus'' is a species of fungus in the genus ''Aspergillus'', and is one of the most common ''Aspergillus'' species to cause disease in individuals with an immunodeficiency.
''Aspergillus fumigatus'', a saprotroph widespread in ...
'' and ''
Cryptococcus neoformans
''Cryptococcus neoformans'' is an encapsulated yeast belonging to the class Tremellomycetes and an obligate aerobe that can live in both plants and animals. Its teleomorph is a filamentous fungus, formerly referred to ''Filobasidiella neoformans' ...
''.
A few years later its immunosuppressive properties were detected. Later studies led to the establishment of rapamycin as a major immunosuppressant against
transplant rejection
Transplant rejection occurs when Organ transplant, transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between don ...
, along with
cyclosporine A
Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is a natural product. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease ...
.
Combining rapamycin with cyclosporine A, enhanced rejection prevention in
renal transplantation
Kidney transplant or renal transplant is the organ transplant of a kidney into a patient with end-stage kidney disease (ESRD). Kidney transplant is typically classified as deceased-donor (formerly known as cadaveric) or living-donor transplantat ...
. Therefore, it was possible to use lower doses of cyclosporine, which minimized
toxicity
Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subst ...
of the drug.
In the 1980s the Developmental Therapeutic Branch of the National Cancer Institute (NCI) evaluated rapamycin and discovered it had an anticancer activity and was non-cytotoxic, but had
cytostatic
Cytostasis (cyto – cell; stasis – stoppage) is the inhibition of cell growth and multiplication. Cytostatic refers to a cellular component or medicine that inhibits cell division.
Cytostasis is an important prerequisite for structured multic ...
activity against several human cancer types.
However, due to unfavorable pharmacokinetic properties, the development of mTOR inhibitors for the treatment of cancer was not successful at that time.
Since then, rapamycin has also shown to be effective for preventing coronary artery
re-stenosis and for the treatment of
neurodegenerative diseases
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
.
First generation mTOR inhibitors
The development of rapamycin as an anticancer agent began again in the 1990s with the discovery of
temsirolimus
Temsirolimus, sold under the brand name Torisel, is an intravenous drug for the treatment of renal cell carcinoma (RCC), developed by Wyeth Pharmaceuticals and approved by the U.S. Food and Drug Administration (FDA) in May 2007, and was also appro ...
(CCI-779). This novel soluble rapamycin derivative had a favorable toxicological profile in animals. More rapamycin derivatives with improved
pharmacokinetics
Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
and reduced
immunosuppressive
Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reacti ...
effects have since then been developed for the
treatment of cancer
Cancer can be treated by surgery, chemotherapy, radiation therapy, hormonal therapy, targeted therapy (including immunotherapy such as monoclonal antibody therapy) and synthetic lethality, most commonly as a series of separate treatments (e.g. ...
.
These rapalogs include
temsirolimus
Temsirolimus, sold under the brand name Torisel, is an intravenous drug for the treatment of renal cell carcinoma (RCC), developed by Wyeth Pharmaceuticals and approved by the U.S. Food and Drug Administration (FDA) in May 2007, and was also appro ...
(CCI-779),
everolimus
Everolimus, sold under the brand name Afinitor among others, is a medication used as an immunosuppressant to prevent rejection of organ transplants and as a targeted therapy in the treatment of renal cell cancer and other tumours.
It is the 40 ...
(RAD001), and
ridaforolimus
Ridaforolimus (also known as AP23573 and MK-8669; formerly known as deforolimus) is an investigational targeted and small-molecule inhibitor of the protein mTOR, a protein that acts as a central regulator of protein synthesis, cell proliferation, ...
(AP-23573) which are being evaluated in cancer
clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
s.
Rapamycin analogs have similar therapeutic effects as rapamycin. However they have improved
hydrophilicity
A hydrophile is a molecule or other molecular entity that is intermolecular force, attracted to water molecules and tends to be dissolution (chemistry), dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clar ...
and can be used for oral and
intravenous administration
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
.
In 2012
National Cancer Institute
The National Cancer Institute (NCI) coordinates the United States National Cancer Program and is part of the National Institutes of Health (NIH), which is one of eleven agencies that are part of the U.S. Department of Health and Human Services. ...
listed more than 200 clinical trials testing the anticancer activity of rapalogs both as
monotherapy
Combination therapy or polytherapy is therapy that uses more than one medication or modality. Typically, the term refers to using multiple therapies to treat a ''single'' disease, and often all the therapies are pharmaceutical (although it can also ...
or as a part of
combination therapy
Combination therapy or polytherapy is therapy that uses more than one medication or modality. Typically, the term refers to using multiple therapies to treat a ''single'' disease, and often all the therapies are pharmaceutical (although it can also ...
for many cancer types.
Rapalogs, which are the first generation mTOR inhibitors, have proven effective in a range of
preclinical
In drug development, preclinical development, also termed preclinical studies or nonclinical studies, is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and drug ...
models. However, the success in
clinical trials
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
is limited to only a few rare cancers.
Animal and clinical studies show that rapalogs are primarily
cytostatic
Cytostasis (cyto – cell; stasis – stoppage) is the inhibition of cell growth and multiplication. Cytostatic refers to a cellular component or medicine that inhibits cell division.
Cytostasis is an important prerequisite for structured multic ...
, and therefore effective as disease stabilizers rather than for regression.
The response rate in solid tumors where rapalogs have been used as a single-agent therapy have been modest. Due to partial mTOR inhibition as mentioned before, rapalogs are not sufficient for achieving a broad and robust anticancer effect, at least when used as
monotherapy
Combination therapy or polytherapy is therapy that uses more than one medication or modality. Typically, the term refers to using multiple therapies to treat a ''single'' disease, and often all the therapies are pharmaceutical (although it can also ...
.
Another reason for the limited success is that there is a feedback loop between mTORC1 and
AKT
Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transc ...
in certain tumor cells. It seems that mTORC1 inhibition by rapalogs fails to repress a
negative feedback
Negative feedback (or balancing feedback) occurs when some function (Mathematics), function of the output of a system, process, or mechanism is feedback, fed back in a manner that tends to reduce the fluctuations in the output, whether caused by ...
loop that results in
phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
and activation of AKT.
These limitations have led to the development of the second generation of mTOR inhibitors.
Rapamycin and rapalogs
Rapamycin and rapalogs (rapamycin derivatives) are
small molecule inhibitors,
which have been evaluated as anticancer agents. The rapalogs have more favorable pharmacokinetic profile compared to rapamycin, the parent drug,
despite the same binding sites for mTOR and FKBP12.
Sirolimus
The bacterial
natural product
A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical syn ...
rapamycin or
sirolimus
Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection, treat a rare lung disease called lymphangioleiomyomatosis, ...
,
a
cytostatic agent, has been used in combination therapy with
corticosteroids
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involve ...
and
cyclosporine
Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is a natural product. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease ...
in patients who received
kidney transplantation
Kidney transplant or renal transplant is the organ transplant of a kidney into a patient with end-stage kidney disease (ESRD). Kidney transplant is typically classified as deceased-donor (formerly known as cadaveric) or living-donor transplantati ...
to prevent
organ rejection
Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient a ...
both in the US
and Europe,
due to its unsatisfying pharmacokinetic properties.
In 2003, the
U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...
approved sirolimus-eluting coronary stents, which are used in patients with narrowing of
coronary arteries
The coronary arteries are the arterial blood vessels of coronary circulation, which transport oxygenated blood to the heart muscle. The heart requires a continuous supply of oxygen to function and survive, much like any other tissue or organ of ...
, or so-called
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...
.
Recently rapamycin has shown effective in the inhibition of growth of several human cancers and murine cell lines.
Rapamycin is the main mTOR inhibitor, but deforolimus (AP23573), everolimus (RAD001), and temsirolimus (CCI-779), are the newly developed rapamycin analogs.
Temsirolimus
The rapamycin analog
temsirolimus
Temsirolimus, sold under the brand name Torisel, is an intravenous drug for the treatment of renal cell carcinoma (RCC), developed by Wyeth Pharmaceuticals and approved by the U.S. Food and Drug Administration (FDA) in May 2007, and was also appro ...
(CCI-779)
is also a noncytotoxic agent which delays tumor proliferation.
Temsirolimus is a
prodrug
A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...
of rapamycin. It is approved by the U.S.
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA)
and the
European Medicines Agency
The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...
(EMA),
for the treatment of renal cell carcinoma (RCC). Temsirolimus has higher water solubility than rapamycin and is therefore administrated by intravenous injection.
It was approved on May 30, 2007, by FDA for the treatment of advanced RCC.
Temsirolimus has also been used in a Phase I clinical trial in conjunction with
neratinib
Neratinib (INN), sold under the brand name Nerlynx, is a tyrosine kinase inhibitor anti-cancer medication used for the treatment of breast cancer.
The most common side effect is diarrhea, which affects nearly all patients. Other common side effe ...
, a small-molecule irreversible pan-HER
tyrosine kinase inhibitor
A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosph ...
. This study enrolled patients being treated for
HER2
Receptor tyrosine-protein kinase erbB-2 is a protein that in humans is encoded by the ''ERBB2'' gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently refer ...
-amplified breast cancer, HER2-mutant non-small-cell lung cancer, and other advanced solid tumors. While common toxicities included
nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
,
stomatitis
Stomatitis is inflammation of the mouth and lips. It refers to any inflammatory process affecting the mucous membranes of the mouth and lips, with or without oral ulceration.
In its widest meaning, stomatitis can have a multitude of different cau ...
, and
anemia
Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...
; responses were noted.
Everolimus
Everolimus
Everolimus, sold under the brand name Afinitor among others, is a medication used as an immunosuppressant to prevent rejection of organ transplants and as a targeted therapy in the treatment of renal cell cancer and other tumours.
It is the 40 ...
is the second novel Rapamycin analog.
Compared with the parent compound
rapamycin
Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection, treat a rare lung disease called lymphangioleiomyomatosis, ...
, everolimus is more selective for the
mTORC1
mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis.
mTOR Complex 1 (mTORC1) is compo ...
protein complex, with little impact on the
mTORC2 complex.
mTORC1 inhibition by everolimus has been shown to normalize tumor blood vessels, to increase
tumor-infiltrating lymphocytes
Tumor-infiltrating lymphocytes (TIL) are white blood cells that have left the bloodstream and cell migration, migrated towards a tumor. They include T cells and B cells and are part of the larger category of ‘tumor-infiltrating immune cells’ wh ...
, and to improve
adoptive cell transfer therapy.
From March 30, 2009 to May 5, 2011 the U.S. FDA approved everolimus for the treatment of advanced renal cell carcinoma after failure of treatment with
sunitinib
Sunitinib, sold under the brand name Sutent, is a medication used to treat cancer. It is a small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal cell carcinoma (RCC) and i ...
or
sorafenib
Sorafenib, sold under the brand name Nexavar, is a kinase inhibitor drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma), advanced primary liver cancer ( hepatocellular carcinoma), FLT3-ITD positive AML and r ...
,
subependymal giant cell astrocytoma
Subependymal giant cell astrocytoma (SEGA, SGCA, or SGCT) is a low-grade astrocytic brain tumor (astrocytoma) that arises within the ventricles of the brain. It is most commonly associated with tuberous sclerosis complex (TSC). Although it is ...
(SEGA) associated with
tuberous sclerosis
Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant genetic disease that causes non-cancerous tumours to grow in the brain and on other vital organs such as the kidneys, heart, liver, eyes, lungs and skin. A combination ...
(TS), and
progressive neuroendocrine tumors of pancreatic origin (PNET).
In July and August 2012, two new indications were approved, for advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane, and pediatric and adult patients with SEGA.
In 2009 and 2011, it was also approved throughout the European Union for advanced breast cancer, pancreatic neuroendocrine tumours, advanced renal cell carcinoma,
and SEGA in patients with tuberous sclerosis.
Ridaforolimus
Ridaforolimus
Ridaforolimus (also known as AP23573 and MK-8669; formerly known as deforolimus) is an investigational targeted and small-molecule inhibitor of the protein mTOR, a protein that acts as a central regulator of protein synthesis, cell proliferation, ...
(AP23573, MK-8669), or deforolimus, is another rapamycin analogue that is not a
prodrug
A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...
for sirolimus.
Like temsirolimus it can be administrated intravenously, and oral formulation is being estimated for treatment of
sarcoma
A sarcoma is a malignant tumor, a type of cancer that arises from transformed cells of mesenchymal (connective tissue) origin. Connective tissue is a broad term that includes bone, cartilage, fat, vascular, or hematopoietic tissues, and sarcom ...
.
Umirolimus
Umirolimus is an immunosuppressant used in drug-eluting stents.
Zotarolimus
Zotarolimus
Zotarolimus (International Nonproprietary Name, INN, codenamed ABT-578) is an immunosuppressant. It is a semi-synthetic derivative of sirolimus (rapamycin). It was designed for use in stents with phosphorylcholine as a carrier. Zotarolimus, or ABT ...
is an immunosuppressant used in
coronary Coronary () may, as shorthand in English, be used to mean:
* Coronary circulation, the system of arteries and veins in mammals
** Coronary artery disease
** Coronary occlusion
** A myocardial infarction, a heart attack
As adjective
* Referring t ...
drug-eluting stents.
Second generation mTOR inhibitors
![Dual inhibitors](https://upload.wikimedia.org/wikipedia/commons/a/a1/Dual_inhibitors.jpg)
The second generation of mTOR inhibitors is known as ATP-competitive mTOR kinase inhibitors.
mTORC1/mTORC2 dual inhibitors such as
torin-1, torin-2 and vistusertib, are designed to compete with ATP in the
catalytic
Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
site of mTOR. They inhibit all of the kinase-dependent functions of mTORC1 and mTORC2 and block the feedback activation of PI3K/AKT signaling, unlike rapalogs, which only target mTORC1.
Development of these drugs has reached clinical trials, although some, such as vistusertib, have been discontinued.
Like rapalogs, they decrease protein
translation
Translation is the communication of the Meaning (linguistic), meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The ...
, attenuate
cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
progression, and inhibit
angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
in many cancer cell lines and also in human cancer. In fact, they have been proven to be more potent than rapalogs.
Theoretically, the most important advantages of these mTOR inhibitors is the considerable decrease of AKT phosphorylation on mTORC2 blockade and in addition to a better inhibition on mTORC1.
However, some drawbacks exist. Even though these compounds have been effective in rapamycin-insensitive cell lines, they have only shown limited success in
KRAS
''KRAS'' (Kirsten rat sarcoma virus) is a gene that provides instructions for making a protein called K-Ras, a part of the RAS/MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cell ...
driven tumors. This suggests that
combinational therapy may be necessary for the treatment of these cancers. Another drawback is also their potential
toxicity
Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subst ...
. These facts have raised concerns about the long term efficacy of these types of inhibitors.
The close interaction of mTOR with the PI3K pathway has also led to the development of mTOR/PI3K dual inhibitors.
Compared with drugs that inhibit either mTORC1 or PI3K, these drugs have the benefit of inhibiting mTORC1, mTORC2, and all the catalytic
isoforms
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...
of PI3K. Targeting both kinases at the same time reduces the
upregulation
In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary proce ...
of PI3K, which is typically produced with an inhibition on mTORC1.
The inhibition of the PI3K/mTOR pathway has been shown to potently block proliferation by inducing
G1 arrest in different tumor cell lines. Strong induction of
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
and
autophagy
Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...
has also been seen. Despite good promising results, there are preclinical evidence that some types of cancers may be insensitive to this dual inhibition. The dual PI3K/mTOR inhibitors are also likely to have increased toxicity.
Mechanism of action
The studies of
rapamycin
Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection, treat a rare lung disease called lymphangioleiomyomatosis, ...
as
immunosuppressive agent
Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent activity of the immune system.
Classification
Immunosuppressive drugs can be classified into ...
enabled us to understand its
mechanism of action
In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targe ...
.
It inhibits
T-cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell rec ...
proliferation and proliferative responses induced by several
cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
s, including
interleukin 1 (IL-1),
IL-2
The Ilyushin Il-2 (Russian language, Russian: Илью́шин Ил-2) is a Ground attack aircraft, ground-attack plane that was produced by the Soviet Union in large numbers during the World War II, Second World War. The word ''shturmovík'' (C ...
,
IL-3,
IL-4,
IL-6,
IGF,
PDGF
Platelet-derived growth factor (PDGF) is one among numerous growth factors that regulate cell growth and division. In particular, PDGF plays a significant role in blood vessel formation, the growth of blood vessels from already-existing blood v ...
, and
colony-stimulating factors (CSFs).
Rapamycin inhibitors and rapalogs can target tumor growth both directly and indirectly. Direct impact of them on cancer cells depend on the concentration of the drug and certain cellular characteristics. The indirect way, is based on interaction with processes required for tumor
angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
.
Effects in cancer cells
![Effects of Rapamycin and its rapalogs in cancer cells](https://upload.wikimedia.org/wikipedia/commons/4/44/Effects_of_Rapamycin_and_its_rapalogs_in_cancer_cells.png)
Rapamycin and rapalogs crosslink the
immunophilin
In molecular biology, immunophilins are endogenous cytosolic peptidyl-prolyl isomerases (PPI) that catalyze the interconversion between the cis and trans isomers of peptide bonds containing the amino acid proline (Pro). They are chaperone molecule ...
FK506
Tacrolimus, sold under the brand name Prograf among others, is an immunosuppressive drug. After allogeneic organ transplant, the risk of organ rejection is moderate. To lower the risk of organ rejection, tacrolimus is given. The drug can also ...
binding protein,
tacrolimus
Tacrolimus, sold under the brand name Prograf among others, is an immunosuppressive drug. After allogeneic organ transplant, the risk of organ rejection is moderate. To lower the risk of organ rejection, tacrolimus is given. The drug can also ...
or FKBP-12, through its
methoxy group
In organic chemistry, a methoxy group is the functional group consisting of a methyl group bound to oxygen. This alkoxy group has the formula .
On a benzene ring, the Hammett equation classifies a methoxy substituent at the ''para'' position as ...
. The rapamycin-FKBP12 complex interferes with FRB domain of mTOR.
Molecular interaction between FKBP12, mTOR, and rapamycin can last for about three days (72 hours). The inhibition of mTOR blocks the binding of the accessory protein raptor (regulatory-associated protein of mTOR) to mTOR, but that is necessary for
downstream
Downstream may refer to:
* Downstream (bioprocess)
* Downstream (manufacturing)
* Downstream (networking)
* Downstream (software development)
* Downstream (petroleum industry)
* Upstream and downstream (DNA), determining relative positions on DNA
* ...
phosphorylation of
S6K1
Ribosomal protein S6 kinase beta-1 (S6K1), also known as p70S6 kinase (p70S6K, p70-S6K), is an enzyme (specifically, a protein kinase) that in humans is encoded by the ''RPS6KB1'' gene. It is a serine/threonine kinase that acts downstream of PIP3 ...
and
4EBP1
Eukaryotic translation initiation factor 4E-binding protein 1 (also known as 4E-BP1) is a protein that in humans is encoded by the ''EIF4EBP1'' gene.
Function
This gene encodes one member of a family of translation repressor proteins. The prot ...
.
As a consequence, S6K1 dephosphorylates, which reduces protein
synthesis
Synthesis or synthesize may refer to:
Science Chemistry and biochemistry
*Chemical synthesis, the execution of chemical reactions to form a more complex molecule from chemical precursors
** Organic synthesis, the chemical synthesis of organ ...
and decreases cell mortality and size. Rapamycin induces dephosphorylation of 4EBP1 as well, resulting in an increase in
p27 and a decrease in
cyclin D1
Cyclin D1 is a protein that in humans is encoded by the ''CCND1'' gene.
Gene expression
The CCND1 gene encodes the cyclin D1 protein. The human CCND1 gene is located on the long arm of chromosome 11 (band 11q13). It is 13,388 base pairs lon ...
expression. That leads to late blockage of G1/S
cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
. Rapamycin has shown to induce cancer cell death by stimulating
autophagy
Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...
or
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
, but the molecular mechanism of apoptosis in cancer cells has not yet been fully resolved. One suggestion of the relation between mTOR inhibition and apoptosis might be through the downstream target S6K1, which can phosphorylate
BAD
Bad or BAD may refer to:
Common meanings
*Evil, the opposite of moral good
* Erroneous, inaccurate or incorrect
* Unhealthy, or counter to well-being
* Antagonist, the threat or obstacle of moral good
Acronyms
* BAD-2, a Soviet armored troll ...
, a pro-apoptotic molecule, on Ser136.
That reaction breaks the binding of BAD to
BCL-XL
B-cell lymphoma-extra large (Bcl-xL), encoded by the BCL2-like 1 gene, is a transmembrane molecule in the mitochondria. It is a member of the Bcl-2 family of proteins, and acts as an anti-apoptotic protein by preventing the release of mitochondr ...
and
BCL2
Bcl-2 (B-cell lymphoma 2), encoded in humans by the ''BCL2'' gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inhibiting (anti-apoptotic) or inducing (pro-apoptotic) apoptosis. ...
, a
mitochondrial
A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is use ...
death inhibitors, resulting in inactivation of BAD
and decreased cell survival.
Rapamycin has also shown to induce
p53
p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
-independent apoptosis in certain types of cancer.
Effects on tumor angiogenesis
![Effects of Rapamycin and rapalogs on endothelial and tumor cells](https://upload.wikimedia.org/wikipedia/commons/b/bd/Effects_of_Rapamycin_and_rapalogs_on_endothelial_and_tumor_cells.png)
Tumor angiogenesis rely on interactions between
endothelial vascular growth factors which can all activate the
PI3K/AKT/mTOR in endothelial cells,
pericyte
Pericytes (previously known as Rouget cells) are multi-functional mural cells of the microcirculation that wrap around the endothelial cells that line the capillaries throughout the body. Pericytes are embedded in the basement membrane of blood ca ...
s, or cancer cells. Example of these growth factors are
angiopoietin 1 (ANG1), ANG 2,
basic fibroblast growth factor (bFGF),
ephrin-B2
Ephrin-B2 is a protein that in humans is encoded by the ''EFNB2'' gene.
Function
This gene encodes a member of the ephrin (EPH) family. The ephrins and EPH-related receptors comprise the largest subfamily of receptor protein-tyrosine kinases an ...
,
vascular endothelial growth factor (VEGF), and members of the
tumor growth factor-β (TGFβ) superfamily. One of the major stimuli of angiogenesis is hypoxia, resulting in activation of
hypoxia-inducible transcription factors (HIFs) and expression of ANG2, bFGF, PDGF, VEGF, and VEGFR. Inhibition of HIF1α translation by preventing PDGF/PDGFR and VEGF/VEGFR can result from mTOR inhibition. A G0-G1 cell-cycle blockage can be the consequence of inactivation of mTOR in hypoxia-activated pericytes and endothelial cells.
There is some evidence that extended therapy with rapamycin may have effect on
AKT
Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transc ...
and mTORC2 as well.
Effects on chemotherapy
Pharmacologic down-regulation of (mTOR) pathway during chemotherapy in a mouse model prevents activation of primordial follicles, preserves ovarian function, and maintains normal fertility using clinically available inhibitors INK and RAD. In that way, it helps to maintain fertility while undergoing chemotherapy treatments. These mTOR inhibitors, when administrated as pretreatment or co-treatment with standard gonadotoxic chemotherapy, helps to maintain ovarian follicles in their primordial state.
Effects on cognition
mTOR promotes the protein synthesis required for
synaptic plasticity
In neuroscience, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity. Since memories are postulated to be represented by vastly interconnected neural circuit ...
.
Studies in cell cultures and
hippocampal
The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, an ...
slices indicate that mTOR inhibition reduces
long-term potentiation
In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons ...
.
mTOR activation can protect against certain
neurodegeneration
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
associated with certain disease conditions.
On the other hand, promotion of
autophagy
Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...
by mTOR inhibition may reduce cognitive decline associated with neurodegeneration.
Moderate reduction of mTOR activity by 25-30% has been shown to improve brain function, suggesting that the relation between mTOR and cognition is optimized with intermediate doses (2.24 mg/kg/day in mice, human equivalent about 0.19 mg/kg/day
), where very high or very low doses impair cognition.
Reduction of the
inflammatory cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
Interleukin 1 beta
Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin" ...
(IL-1β) in mice by mTOR inhibition (with rapamycin in doses of 20 mg/kg/day, human equivalent about 1.6 mg/kg/day
) has been shown to enhance learning and memory.
Although IL-1β is required for memory, IL-1β normally increases with age, impairing cognitive function.
Structure activity relationship
The pipecolate region of rapamycin structure seems necessary for rapamycin-binding to
FKBP12
Peptidyl-prolyl cis-trans isomerase FKBP1A is an enzyme that in humans is encoded by the ''FKBP1A'' gene.
Function
The protein encoded by this gene is a member of the immunophilin protein family, which play a role in immunoregulation and basic ...
. This step is required for further binding of rapamycin to the mTOR kinase, which is the key enzyme in many biological actions of rapamycin.
The high affinity of rapamycin binding to FKBP12 is explained by number of
hydrogen bond
In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a ...
s through two different
hydrophobic
In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, th ...
binding pockets, and this has been revealed by X-ray crystal structure of the compound bound to the
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
. The structural characteristics common to temsirolimus and sirolimus; the
pipecolic acid
Pipecolic acid (piperidine-2-carboxylic acid) is an organic compound with the formula HNC5H9CO2H. It is a carboxylic acid derivative of piperidine and, as such, an amino acid, although not one encoded genetically. Like many other α-amino acids, p ...
, tricarbonyl region from C13-C15, and
lactone
Lactones are cyclic carboxylic esters, containing a 1-oxacycloalkan-2-one structure (), or analogues having unsaturation or heteroatoms replacing one or more carbon atoms of the ring.
Lactones are formed by intramolecular esterification of the co ...
functionalities play the key role in binding groups with the FKBP12.
The most important
hydrogen bonds
In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a ...
are the lactone carbonyl oxygen at C-21 to the backbone NH of
Ile56, amide carbonyl at C-15 to the phenolic group on the sidechain of
Tyr82, and the hydroxyl proton at the
hemiketal
A hemiacetal or a hemiketal has the general formula R1R2C(OH)OR, where R1 or R2 is hydrogen or an organic substituent. They generally result from the addition of an alcohol to an aldehyde or a ketone, although the latter are sometimes called hemi ...
carbon, C-13, to the sidechain of
Asp37.
![Sirolimus binding sites](https://upload.wikimedia.org/wikipedia/commons/6/69/Sirolimus_binding_sites.svg)
Structural changes to the rapamycin structure can affect binding to mTOR. This could include both direct and indirect binding as a part of binding to FKBP12. Interaction of the FKBP12-rapamycin complex with mTOR corresponds with conformational flexibility of the effector domain of rapamycin. This domain consists of molecular regions that make hydrophobic interactions with the FKB domain and
triene
In organic chemistry, polyenes are poly- unsaturated, organic compounds that contain at least three alternating double () and single () carbon–carbon bonds. These carbon–carbon double bonds interact in a process known as conjugation, resultin ...
region from C-1-C-6, methoxy group at C-7, and
methyl group
In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many ...
s at C-33, C-27 and C-25. All changes of the macrolide ring can have unpredictable effects on binding and therefore, make determination of
SAR
SAR or Sar may refer to:
Places
* Sar (river), Galicia, Spain
* Sar, Bahrain, a residential district
* Sar, Iran (disambiguation), several places in Iran
* Sar, Tibet, Tibet Autonomous Region of China
* Šar Mountains, in southeastern Europe
...
for rapalogs problematic.
Rapamycin contains no functional groups that
ionize
Ionization, or Ionisation is the process by which an atom or a molecule acquires a negative or positive charge by gaining or losing electrons, often in conjunction with other chemical changes. The resulting electrically charged atom or molecule i ...
in the
pH range 1-10 and therefore, are rather insoluble in water.
Despite its effectiveness in preclinic cancer models, its poor solubility in water, stability, and the long half-life elimination made its parenteral use difficult, but the development of soluble rapamycin analogs vanquished various barriers.
Nonetheless, the rapamycin analogs that have been approved for human use are modified at C-43 hydroxyl group and show improvement in
pharmacokinetic
Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
parameters as well as drug properties, for example, solubility.
Rapamycin and temsirolimus have similar chemical structures and bind to FKBP12, though their mechanism of action differs.
Temsirolimus is a dihydroxymethyl propionic
acid
In computer science, ACID ( atomicity, consistency, isolation, durability) is a set of properties of database transactions intended to guarantee data validity despite errors, power failures, and other mishaps. In the context of databases, a sequ ...
ester
In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...
of rapamycin, and its first derivative.
Therefore, it is more water-soluble, and due to its water solubility it can be given by intravenous formulation.
Everolimus has O-2 hydroxyethyl chain substitution and deforolimus has a
phosphine oxide
Phosphine oxides are phosphorus compounds with the formula OPX3. When X = alkyl or aryl, these are organophosphine oxides. Triphenylphosphine oxide is an example. An inorganic phosphine oxide is phosphoryl chloride (POCl3).
Structure and bonding ...
substitution at position C-43 in the lactone ring of rapamycin.
Deforolimus (Ridaforolimus ) has C43 secondary alcohol moiety of the cyclohexyl group of Rapamycin that was substituted with phosphonate and phosphinate groups, preventing the high-affinity binding to mTOR and FKBP. Computational modelling studies helped the synthesise of the compound.
Adverse events
Treatment with mTOR inhibitors can be complicated by adverse events. The most frequently occurring adverse events are stomatitis, rash, anemia, fatigue, hyperglycemia/hypertriglyceridemia, decreased appetite, nausea, and diarrhea. Additionally,
interstitial lung disease
Interstitial lung disease (ILD), or diffuse parenchymal lung disease (DPLD), is a group of respiratory diseases affecting the interstitium (the tissue and space around the alveoli (air sacs)) of the lungs. It concerns alveolar epithelium, pulmo ...
is an adverse event of particular importance. mTORi-induced ILD often is asymptomatic (with
ground glass abnormalities on chest CT) or mild symptomatic (with a non-productive cough), but can be very severe as well. Even fatalities have been described. Careful diagnosis and treatment, therefore, is essential. Recently, a new diagnostic and therapeutic management approach has been proposed.
Biomarkers
Identification of predictive
biomarker
In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...
s of efficacy for tumor types that are sensitive to mTOR inhibitors remains a major issue.
Possible predictive biomarkers for
tumor response to mTOR inhibitors, as have been described in
glioblastoma
Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ch ...
,
breast
The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues.
In females, it serves as the mammary gland, which produces and secret ...
and
prostate cancer
Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...
cells, may be the differential expression of mTOR pathway proteins,
PTEN,
AKT
Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transc ...
, and S6.
Thus, this data is based on preclinical assays, based on ''
in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
'' cultured tumor cell lines, which suggest that the effects of mTOR inhibitors may be more pronounced in cancers displaying loss of PTEN functions or
PIK3CA mutations. However, the use of PTEN, PIK3CA
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
s, and AKT–phospho status for predicting rapalog sensitivity has not been fully validated in clinic. To date, attempts to identify biomarkers of rapalog response have been unsuccessful.
Sensitivity
Clinical and translational data suggest that sensitive tumor types, with adequate parameters and functional
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
pathways, might not need high doses of mTOR inhibitors to trigger apoptosis. In most cases, cancer cells might only be partially sensitive to mTOR inhibitors due to redundant
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
or lack of functional apoptosis signaling pathways. In situations like this, high doses of mTOR inhibitors might be required. In a recent study of patients with
Renal cell carcinoma
Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. RCC is the most common type of kidney cancer in adults, resp ...
, resistance to Temsirolimus was associated with low levels of p-AKT and p-S6K1, that play the key role in mTOR activation. These data strongly suggests number of tumors with an activated PI3K/AKT/mTOR signaling pathway that does not respond to mTOR inhibitors. For future studies, it is recommended to exclude patients with low or negative p-AKT levels from trials with mTOR inhibitors.
Current data is insufficient to predict sensitivity of tumors to rapamycin. However, the existing data allows us to characterize tumors that might not respond to rapalogs.
ATP-competitive mTOR kinase inhibitors
These second generation mTOR inhibitors bind to ATP-binding site in mTOR kinase domain required for the functions of both
mTORC1
mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis.
mTOR Complex 1 (mTORC1) is compo ...
and
mTORC2, and result in
downregulation
In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary proc ...
of mTOR signaling pathway. Due to PI3K and mTORC2 ability to regulate AKT phosphorylation, these two compounds play a key role in minimizing the feedback activation of AKT.
mTOR/PI3K dual inhibitors
Several, so-called mTOR/PI3K dual inhibitors (TPdIs), have been developed and are in early-stage
preclinical trials and show promising results. Their development has been benefited from previous studies with PI3K-selective inhibitors.
The activity of these small molecules from rapalog activity differs in the way by blocking both mTORC1-dependent phospholylation of S6K1 and mTORC2-dependent phosphorylation of AKT Ser473 residue.
![Dactolisib](https://upload.wikimedia.org/wikipedia/commons/9/9f/Dactolisib.svg)
Dual mTOR/PI3K inhibitors include
dactolisib
Dactolisib (codenamed NVP-BEZ235 and BEZ-235, also known as RTB101) is an imidazoquinoline derivative acting as a PI3K inhibitor. It also inhibits mTOR. It is being investigated as a possible cancer treatment.
It has been shown to be toxic to ...
,
voxtalisib, BGT226, SF1126, PKI-587 and many more. For example,
Novartis
Novartis AG is a Swiss-American multinational pharmaceutical corporation based in Basel, Switzerland and
Cambridge, Massachusetts, United States (global research).name="novartis.com">https://www.novartis.com/research-development/research-loc ...
has developed the compound NVPBE235 that was reported to inhibit tumor growth in various preclinical models. It enhances antitumor activity of some other drugs such as
vincristine
Vincristine, also known as leurocristine and marketed under the brand name Oncovin among others, is a chemotherapy medication used to treat a number of types of cancer. This includes acute lymphocytic leukemia, acute myeloid leukemia, Hodgkin's ...
.
Dactolisib seems to inhibit effectively both wild-type and mutant form of PI3KCA, which suggests its use towards wide types of tumors. Studies have shown superior antiproliferative activity to rapalogs and ''
in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
'' models have confirmed these potent
antineoplastic effects of dual mTOR/PI3K inhibitors.
These inhibitors target
isoforms
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...
of PI3K (p110α, β and γ) along with ATP-binding sites of mTORC1 and mTORC2 by blocking PI3K/AKT signaling, even in cancer types with mutations in this pathway.
mTORC1/mTORC2 dual inhibitors (TORCdIs)
![Sapanisertib](https://upload.wikimedia.org/wikipedia/commons/7/71/Sapanisertib.svg)
New mTOR-specific inhibitors came forth from screening and
drug discovery
In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered.
Historically, drugs were discovered by identifying the active ingredient from traditional remedies or by ...
efforts. These compounds block activity of both mTOR complexes and are called mTORC1/mTORC2 dual inhibitors.
Compounds with this characteristics such as
sapanisertib (codenamed INK128), AZD8055, and AZD2014 have entered
clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
s.
A series of these mTOR kinase inhibitors have been studied. Their structure is derived from morpholino pyrazolopyrimidine scaffold.
Improvements of this type of inhibitors have been made by exchanging the morpholines with bridged morpholines in pyrazolopyrimidine inhibitors and results showed increased selectivity to mTOR by 26000 fold.
Limitations of new generation mTOR inhibitors
Although the new generation of mTOR inhibitors hold great promise for anticancer therapy and are rapidly moving into clinical trials, there are many important issues that determine their success in the clinic. First of all predictable biomarkers for benefit of these inhibitors are not available. It appears that genetic determinants predispose cancer cells to be sensitive or resistant to these compounds. Tumors that depend on PI3K/mTOR pathway should respond to these agents but it is unclear if compounds are effective in cancers with distinct genetic lesions.
Inhibition of mTOR is a promising strategy for treatment of number of cancers. Limited clinical activity of selective mTORC1 agents have made them unlikely to have impact in cancer treatment. The development of competitive ATP-catalytic inhibitors have the ability to block both mTORC1 and mTORC2.
Future
The limitations of currently available rapalogs have led to new approaches to mTOR targeting. Studies suggest that mTOR inhibitors may have anticancer activity in many cancer types, such as
RCC,
neuroendocrine tumors
Neuroendocrine tumors (NETs) are neoplasms that arise from cells of the endocrine (hormonal) and nervous systems. They most commonly occur in the intestine, where they are often called carcinoid tumors, but they are also found in the pancreas, lung ...
,
breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...
,
hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide.
It occurs in t ...
,
sarcoma
A sarcoma is a malignant tumor, a type of cancer that arises from transformed cells of mesenchymal (connective tissue) origin. Connective tissue is a broad term that includes bone, cartilage, fat, vascular, or hematopoietic tissues, and sarcom ...
, and
large B-cell lymphoma
The large-cell lymphomas have large cells. One classification system for lymphomas divides the diseases according to the size of the white blood cells that have turned cancerous. A large cell, in this context, has a diameter of 17 to 20 μm. ...
.
One major limitation for the development of mTOR inhibition therapy is that biomarkers are not presently available to predict which patient will respond to them. A better understanding of the molecular mechanisms that are involved in the response of cancer cells to mTOR inhibitors are still required so this can be possible.
A way to overcome the resistance and improve efficacy of mTOR targeting agents may be with stratification of patients and selection of drug combination therapies. This may lead to a more effective and personalized cancer therapy.
Although further research is needed, mTOR targeting still remains an attractive and promising therapeutic option for the treatment of cancer.
See also
*
Mammalian target of rapamycin (mTOR)
*
PI3K/AKT/mTOR pathway
The PI3K/AKT/mTOR pathway is an intracellular signaling pathway important in regulating the cell cycle. Therefore, it is directly related to cellular quiescence, proliferation, cancer, and longevity. PI3K activation phosphorylates and activates A ...
*
Akt/PKB signaling pathway The Akt signaling pathway or PI3K-Akt signaling pathway is a signal transduction pathway that promotes survival and growth in response to extracellular signals. Key proteins involved are PI3K (phosphatidylinositol 3-kinase) and Akt ( protein kinas ...
*
PI3K inhibitor
Phosphoinositide 3-kinase inhibitors (PI3K inhibitors) are a class of medical drugs that are mainly used to treat advanced cancers. They function by inhibiting one or more of the phosphoinositide 3-kinase (PI3K) enzymes, which are part of the PI ...
References
Further reading
*
*
{{Major Drug Groups
Signal transduction
Tor signaling pathway
Human proteins
Antineoplastic drugs
Oncology
Cancer treatments
mTOR inhibitors
mTOR inhibitors are a drug class, class of drugs that inhibit the mechanistic target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that belongs to the family of Phosphoinositide 3-kinase, phosphatidylinositol-3 kinase ( ...