Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
s involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer.
PI3Ks are a family of related intracellular
signal transducer
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 ...
enzymes capable of phosphorylating the 3 position
hydroxyl
In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...
group of the
inositol
Inositol, or more precisely ''myo''-inositol, is a carbocyclic sugar that is abundant in the brain and other mammalian tissues; it mediates cell signal transduction in response to a variety of hormones, neurotransmitters, and growth factors and ...
ring of
phosphatidylinositol
Phosphatidylinositol (or Inositol Phospholipid) consists of a family of lipids as illustrated on the right, where red is x, blue is y, and black is z, in the context of independent variation, a class of the phosphatidylglycerides. In such molecul ...
(PtdIns). The pathway, with
oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. PIK3CA and
tumor suppressor gene
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
PTEN, is implicated in the sensitivity of cancer tumors to
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
and
IGF1
Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in molecular structure to insulin which plays an important role in childhood growth, and has anabolic effects in adults.
IGF-1 is a protein that in humans is ...
, and in
calorie restriction
Calorie restriction (caloric restriction or energy restriction) is a dietary regimen that reduces intake of energy from caloric foods & beverages without incurring malnutrition. "Reduce" can be defined relative to the subject's previous intake be ...
.
Discovery
The discovery of PI3Ks by
Lewis Cantley and colleagues began with their identification of a previously unknown phosphoinositide kinase associated with the
polyoma
''Polyomaviridae'' is a family of viruses whose natural hosts are primarily mammals and birds. As of 2020, there are six recognized genera and 117 species, five of which are unassigned to a genus. 14 species are known to infect humans, while othe ...
middle T protein. They observed unique substrate specificity and chromatographic properties of the products of the lipid kinase, leading to the discovery that this phosphoinositide kinase had the unprecedented ability to phosphorylate phosphoinositides on the 3' position of the inositol ring.
Subsequently, Cantley and colleagues demonstrated that in vivo the enzyme prefers PtdIns(4,5)P2 as a substrate, producing the novel phosphoinositide
PtdIns(3,4,5)P3
Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)''P''3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2). It is a phospholipid t ...
previously identified in neutrophils.
Classes
The PI3K family is divided into four different classes:
Class I,
Class II,
Class III, and Class IV. The classifications are based on primary structure, regulation, and ''in vitro'' lipid substrate specificity.
Class I
Class I PI3Ks catalyze the conversion of
phosphatidylinositol (4,5)-bisphosphate
Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)''P''2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)''P''2 is enriched at the plasma membrane where it is a substrate for a number of ...
(PI(4,5)P
2) into
phosphatidylinositol (3,4,5)-trisphosphate
Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)''P''3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2). It is a phospholipid th ...
(PI(3,4,5)P
3) in vivo. While in vitro, they have also been shown to convert
phosphatidylinositol
Phosphatidylinositol (or Inositol Phospholipid) consists of a family of lipids as illustrated on the right, where red is x, blue is y, and black is z, in the context of independent variation, a class of the phosphatidylglycerides. In such molecul ...
(PI) into
phosphatidylinositol 3-phosphate
Phosphatidylinositol 3-phosphate (PtdIns3''P'') is a phospholipid found in cell membranes that helps to recruit a range of proteins, many of which are involved in protein trafficking, to the membranes. It is the product of both the class II and II ...
(PI3P) and
phosphatidylinositol 4-phosphate Phosphatidylinositol-4-phosphate (PtdIns4''P'', PI-4-P, PI4P, or PIP) is a precursor of phosphatidylinositol (4,5)-bisphosphate. PtdIns4''P'' is prevalent in the membrane of the Golgi apparatus.
In the Golgi apparatus, PtdIns4''P'' binds to the GT ...
(PI4P) into
phosphatidylinositol (3,4)-bisphosphate
Phosphatidylinositol (3,4)-bisphosphate (PtdIns(3,4)''P''2) is a minor phospholipid component of cell membranes, yet an important second messenger. The generation of PtdIns(3,4)''P''2 at the plasma membrane activates a number of important cell sig ...
(PI(3,4)P
2), these reactions are strongly disfavoured in vivo.
The PI3K is activated by
G protein-coupled receptors
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
and
tyrosine kinase receptors
Receptor tyrosine kinases (RTKs) are the high-dissociation constant#Protein-ligand binding, affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the hu ...
.
Class I PI3Ks are
heterodimeric
In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...
molecules composed of a regulatory and a catalytic
subunit; they are further divided between IA and IB subsets on sequence similarity. Class IA PI3Ks are composed of a heterodimer between a p110 catalytic subunit and a shorter regulatory subunit (often p85). There are five variants of the regulatory subunit: the three
splice variants p85α, p55α, and p50α,
p85β
Phosphatidylinositol 3-kinase regulatory subunit beta is an enzyme that in humans is encoded by the ''PIK3R2'' gene.
A recent study on gene expression indicated that the PIK3R2 gene might have a key role in pan-cancer prognosis.
Interactions
...
, and
p55γ. There are also three variants of the p110 catalytic subunit designated p110α, β, or δ catalytic subunit. The first three regulatory subunits are all splice variants of the same gene (''Pik3r1''), the other two being expressed by other genes (Pik3r2 and Pik3r3, p85β, and p55γ, respectively). The most highly expressed regulatory subunit is p85α; all three catalytic subunits are expressed by separate genes (''Pik3ca'', ''Pik3cb'', and ''Pik3cd'' for
p110α
The phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (the HUGO-approved official symbol = PIK3CA; HGNC ID, HGNC:8975), also called p110α protein, is a class I PI 3-kinase catalytic subunit. The human p110α protein is enco ...
,
p110β, and
p110δ
Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta isoform also known as phosphoinositide 3-kinase (PI3K) delta isoform or p110δ is an enzyme that in humans is encoded by the ''PIK3CD'' gene.
p110δ regulates immune function. ...
, respectively). The first two p110 isoforms (α and β) are expressed in all cells, but p110δ is expressed primarily in
leukocytes
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
, and it has been suggested that it evolved in parallel with the adaptive immune system. The regulatory p101 and catalytic
p110γ subunits comprise the class IB PI3Ks and are encoded by a single gene each (''Pik3cg'' for
p110γ and ''Pik3r5'' for p101).
The p85 subunits contain
SH2 and
SH3 domains (). The SH2 domains bind preferentially to phosphorylated tyrosine residues in the amino acid sequence context Y-X-X-M.
Classes II and III
Class II and
III PI3Ks are differentiated from the Class I by their structure and function. The distinct feature of Class II PI3Ks is the C-terminal C2 domain. This domain lacks critical
Asp residues to coordinate binding of Ca
2+, which suggests class II PI3Ks bind lipids in a Ca
2+-independent manner.
Class II comprises three catalytic isoforms (C2α, C2β, and C2γ), but, unlike Classes I and III, no regulatory proteins. Class II catalyse the production of PI(3)P from PI and PI(3,4)P
2 from PI(4)P; however, little is known about their role in immune cells. PI(3,4)P
2 has, however, been shown to play a role in the invagination phase of clathrin-mediated endocytosis.
C2α and C2β are expressed through the body, but expression of C2γ is limited to
hepatocytes
A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass.
These cells are involved in:
* Protein synthesis
* Protein storage
* Transformation of carbohydrates
* Synthesis of cholesterol, b ...
.
Class III PI3Ks produce only PI(3)P from PI
but are more similar to Class I in structure, as they exist as heterodimers of a catalytic (
Vps34 Class III PI 3-kinase is a subgroup of the enzyme family, phosphoinositide 3-kinase that share a common protein domain structure, substrate specificity and method of activation.
There is only one known class III PI 3-kinase, Vps34, which is also th ...
) and a regulatory (Vps15/p150) subunits. Class III seems to be primarily involved in the trafficking of proteins and vesicles. There is, however, evidence to show that they are able to contribute to the effectiveness of several process important to immune cells, not least
phagocytosis
Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is ...
.
Class IV
A group of more distantly related enzymes is sometimes referred to as class IV PI3Ks. It is composed of
ataxia telangiectasia mutated
ATM serine/threonine kinase or Ataxia-telangiectasia mutated, symbol ATM, is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks. It phosphorylates several key proteins that initiate activation of the DNA ...
(ATM),
ataxia telangiectasia and Rad3 related
Serine/threonine-protein kinase ATR also known as ataxia telangiectasia and Rad3-related protein (ATR) or FRAP-related protein 1 (FRP1) is an enzyme that, in humans, is encoded by the ''ATR'' gene. It is a large kinase of about 301.66 kDa. ATR bel ...
(ATR),
DNA-dependent protein kinase (DNA-PK) and
mammalian 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). They are protein serine/threonine kinases.
Human genes
Mechanism
The various 3-phosphorylated
phosphoinositides
Phosphatidylinositol (or Inositol Phospholipid) consists of a family of lipids as illustrated on the right, where red is x, blue is y, and black is z, in the context of independent variation, a class of the phosphatidylglycerides. In such molecul ...
that are produced by PI3Ks (
PtdIns3P
Phosphatidylinositol 3-phosphate (PtdIns3''P'') is a phospholipid found in cell membranes that helps to recruit a range of proteins, many of which are involved in protein trafficking, to the membranes. It is the product of both the class II and II ...
,
PtdIns(3,4)P2,
PtdIns(3,5)P2, and
PtdIns(3,4,5)P3
Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)''P''3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2). It is a phospholipid t ...
) function in a mechanism by which an assorted group of signalling proteins, containing
PX domain
The PX domain is a phosphoinositide-binding structural domain involved in targeting of proteins to cell membranes.
This domain was first found in P40phox and p47phox domains of NADPH oxidase (phox stands for phagocytic oxidase). It was also ident ...
s,
pleckstrin homology domain
Pleckstrin homology domain (PH domain) or (PHIP) is a protein domain of approximately 120 amino acids that occurs in a wide range of proteins involved in intracellular signaling or as constituents of the cytoskeleton.
This domain can bind phospha ...
s (PH domains),
FYVE domains or other phosphoinositide-binding domains, are recruited to various cellular membranes.
Function
PI3Ks have been linked to an extraordinarily diverse group of cellular functions, including cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. Many of these functions relate to the ability of class I PI3Ks to activate
protein kinase B
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 ...
(PKB, aka Akt) as in the
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 ...
. The
p110δ
Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta isoform also known as phosphoinositide 3-kinase (PI3K) delta isoform or p110δ is an enzyme that in humans is encoded by the ''PIK3CD'' gene.
p110δ regulates immune function. ...
and
p110γ isoforms regulate different aspects of immune responses. PI3Ks are also a key component of the
insulin signaling pathway. Hence there is great interest in the role of PI3K signaling in
diabetes mellitus
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
. PI3K is also involved in interleukin signalling (IL4)
Mechanism
The
pleckstrin homology domain
Pleckstrin homology domain (PH domain) or (PHIP) is a protein domain of approximately 120 amino acids that occurs in a wide range of proteins involved in intracellular signaling or as constituents of the cytoskeleton.
This domain can bind phospha ...
of
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 ...
binds directly to
PtdIns(3,4,5)P3
Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)''P''3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2). It is a phospholipid t ...
and
PtdIns(3,4)P2, which are produced by activated PI3Ks. Since PtdIns(3,4,5)P3 and PtdIns(3,4)P2 are restricted to the plasma membrane, this results in translocation of AKT to the plasma membrane. Likewise, the
phosphoinositide-dependent kinase-1
In the field of biochemistry, PDPK1 refers to the protein 3-phosphoinositide-dependent protein kinase-1, an enzyme which is encoded by the ''PDPK1'' gene in humans. It is implicated in the development and progression of melanomas.
Function
P ...
(PDK1 or, rarely referred to as PDPK1) also contains a pleckstrin homology domain that binds directly to PtdIns(3,4,5)P3 and PtdIns(3,4)P2, causing it to also translocate to the plasma membrane upon PI3K activation. The interaction of activated PDK1 and AKT allows AKT to become phosphorylated by PDK1 on threonine 308, leading to partial activation of AKT. Full activation of AKT occurs upon phosphorylation of serine 473 by the TORC2 complex of the
mTOR
The mammalian target of sirolimus, 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 ''MT ...
protein kinase.
The
PI3K/AKT pathway has been shown to be required for an extremely diverse array of cellular activities - most notably cellular proliferation and survival. For example, it was shown to be involved in the protection of astrocytes from ceramide-induced apoptosis.
Many other proteins have been identified that are regulated by PtdIns(3,4,5)P3, including
Bruton's tyrosine kinase
Bruton's tyrosine kinase (abbreviated Btk or BTK), also known as tyrosine-protein kinase BTK, is a tyrosine kinase that is encoded by the ''BTK'' gene in humans. BTK plays a crucial role in B cell development.
Structure
BTK contains five differ ...
(BTK), General Receptor for Phosphoinositides-1 (GRP1), and the
O-linked N-acetylglucosamine (O-GlcNAc) transferase.
PtdIns(3,4,5)P3 also activates guanine‐nucleotide exchange factors (GEFs) that activate the GTPase Rac1, leading to
actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over ...
polymerization and cytoskeletal rearrangement.
Cancers
The
class IA PI3K p110α
The phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (the HUGO-approved official symbol = PIK3CA; HGNC ID, HGNC:8975), also called p110α protein, is a class I PI 3-kinase catalytic subunit. The human p110α protein is enco ...
is mutated in many cancers. Many of these mutations cause the kinase to be more active. It is the single most mutated kinase 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 ...
, the most malignant primary brain tumor.
The PtdIns(3,4,5)''P''
3 phosphatase
PTEN that antagonises PI3K signaling is absent from many tumours. In addition, the epidermal growth factor receptor
EGFR that functions upstream of PI3K is mutationally activated or overexpressed in cancer.
Hence, PI3K activity contributes significantly to
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 the development of
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
. It has been shown that malignant B cells maintain a "tonic" activity of PI3K/Akt axis via upregulation of an adaptor protein GAB1, and this also allows B cells to survive targeted therapy with BCR inhibitors.
Learning and memory
PI3Ks have also been implicated in
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 ...
(LTP). Whether they are required for the expression or the induction of LTP is still debated. In mouse hippocampal CA1 neurons, certain PI3Ks are complexed with
AMPA receptor
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor, AMPAR, or quisqualate receptor) is an ionotropic receptor, ionotropic transmembrane receptor for glutamate (iGluR) that mediates fast synapse, synap ...
s and compartmentalized at the postsynaptic density of glutamatergic synapses. PI3Ks are phosphorylated upon
NMDA receptor
The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA rece ...
-dependent CaMKII activity, and it then facilitates the insertion of AMPA-R GluR1 subunits into the plasma membrane. This suggests that PI3Ks are required for the expression of LTP. Furthermore, PI3K inhibitors abolished the expression of LTP in rat hippocampal CA1, but do not affect its induction. Notably, the dependence of late-phase LTP expression on PI3Ks seems to decrease over time.
However, another study found that PI3K inhibitors suppressed the induction, but not the expression, of LTP in mouse hippocampal CA1. The
PI3K pathway
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 ...
also recruits many other proteins downstream, including
mTOR
The mammalian target of sirolimus, 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 ''MT ...
,
GSK3β
Glycogen synthase kinase-3 beta, (GSK-3 beta), is an enzyme that in humans is encoded by the ''GSK3B'' gene. In mice, the enzyme is encoded by the Gsk3b gene. Abnormal regulation and expression of GSK-3 beta is associated with an increased suscept ...
, and
PSD-95
PSD-95 (postsynaptic density protein 95) also known as SAP-90 (synapse-associated protein 90) is a protein that in humans is encoded by the ''DLG4'' (discs large homolog 4) gene.
PSD-95 is a member of the membrane-associated guanylate kinase
T ...
.
The
PI3K-mTOR pathway leads to the phosphorylation of
p70S6K, a kinase that facilitates translational activity, further suggesting that PI3Ks are required for the protein-synthesis phase of LTP induction instead.
PI3Ks interact with the
insulin receptor substrate Insulin receptor substrate (IRS) is an important ligand in the insulin response of human cells.
IRS-1, for example, is an IRS protein that contains a phosphotyrosine binding-domain ( PTB-domain). In addition, the insulin receptor
The insulin re ...
(IRS) to regulate glucose uptake through a series of phosphorylation events.
PI 3-kinases as protein kinases
Many PI3Ks appear to have a serine/threonine kinase activity ''in vitro''; however, it is unclear whether this has any role ''in vivo''.
Inhibition
All PI3Ks are inhibited by the drugs
wortmannin
Wortmannin, a steroid metabolite of the fungi ''Penicillium funiculosum'', '' Talaromyces wortmannii'', is a non-specific, covalent inhibitor of phosphoinositide 3-kinases (PI3Ks). It has an ''in vitro'' inhibitory concentration (''IC''50) of a ...
and
LY294002
LY294002 is a morpholine-containing chemical compound that is a potent inhibitor of numerous proteins, and a strong inhibitor of phosphoinositide 3-kinases (PI3Ks). It is generally considered a non-selective research tool, and should not be used ...
, although certain members of the class II PI3K family show decreased sensitivity.
Wortmannin
Wortmannin, a steroid metabolite of the fungi ''Penicillium funiculosum'', '' Talaromyces wortmannii'', is a non-specific, covalent inhibitor of phosphoinositide 3-kinases (PI3Ks). It has an ''in vitro'' inhibitory concentration (''IC''50) of a ...
shows better efficiency than
LY294002
LY294002 is a morpholine-containing chemical compound that is a potent inhibitor of numerous proteins, and a strong inhibitor of phosphoinositide 3-kinases (PI3Ks). It is generally considered a non-selective research tool, and should not be used ...
on the hotspot mutation positions (GLU542, GLU545, and HIS1047)
PI3K inhibitors as therapeutics
As
wortmannin
Wortmannin, a steroid metabolite of the fungi ''Penicillium funiculosum'', '' Talaromyces wortmannii'', is a non-specific, covalent inhibitor of phosphoinositide 3-kinases (PI3Ks). It has an ''in vitro'' inhibitory concentration (''IC''50) of a ...
and
LY294002
LY294002 is a morpholine-containing chemical compound that is a potent inhibitor of numerous proteins, and a strong inhibitor of phosphoinositide 3-kinases (PI3Ks). It is generally considered a non-selective research tool, and should not be used ...
are broad-range
inhibitors of PI3Ks and a number of unrelated proteins at higher concentrations, they are too toxic to be used as therapeutics. A number of pharmaceutical companies have thus developed PI3K isoform-specific inhibitors. As of January 2019, three PI3K inhibitors are approved by the
FDA
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 ...
for routine clinical use in humans: the PIK3CD inhibitor
idelalisib
Idelalisib, sold under the brand name Zydelig, is a medication used to treat certain blood cancers.
The substance acts as a phosphoinositide 3-kinase inhibitor; more specifically, it blocks P110δ, the delta isoform of the enzyme phosphoinositi ...
(July 2014
NDA 206545, the dual PIK3CA and PIK3CD inhibitor
copanlisib
Copanlisib (trade name Aliqopa ; codenamed BAY 80-6946) is a drug which is approved by US FDA for the treatment of adult patients experiencing relapsed follicular lymphoma who have received at least two prior systemic therapies.
Copanlisib has b ...
(September 2017
NDA 209936, and the dual PIK3CD and PIK3CG inhibitor
duvelisib
Duvelisib, sold under the brand name Copiktra, is a medication used to treat chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and follicular lymphoma after other treatments have failed. It is taken by mouth. It is a PI3 kina ...
(September 2018
NDA 211155. Co-targeted inhibition of the pathway with other pathways such as MAPK or PIM has been highlighted as a promising anti-cancer therapeutic strategy, which could offer benefit over the monotherapeutic approach by circumventing compensatory signalling, slowing the development of resistance and potentially allowing reduction of dosing.
See also
*
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 ...
References
Further reading
*
*
*
*
External links
*
* to explore the structure in interactive 3D
*
PI3K/Akt Signaling Pathway
{{DEFAULTSORT:Phosphoinositide 3-Kinase
EC 2.7.1
Oncology