Pyr1 (LIMINIB) is an

organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. The ...

composed of carbon, hydrogen, oxygen and nitrogen that inhibits the

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 ...

LIM kinase. It was discovered by the Cure and Inserm Institute,

CNRS The French National Centre for Scientific Research (french: link=no, Centre national de la recherche scientifique, CNRS) is the French state research organisation and is the largest fundamental science agency in Europe. In 2016, it employed 31,637 ...

and CEA in the 2010s. The studies ''in vitro'' and with animals, prove that this molecule has a completely new mechanism of action that could be used against chemotherapy resistant cells. Pyr1 reversibly stabilizes

microtubule Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nm and have an inner diameter between 11 an ...

s, blocks

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 ...

microfilament dynamics and inhibits

cell motility Motility is the ability of an organism to move independently, using metabolic energy. Definitions Motility, the ability of an organism to move independently, using metabolic energy, can be contrasted with sessility, the state of organisms th ...

''in vitro''. These characteristics confer not only anticancer properties but also the capacity to prevent

metastasis Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...

to the molecule.

Description and properties

Pyr1 is classified as a small molecule that belongs to the group of pyridocarbazoles.Pyridocarbazoles
/ref> Its small size gives it special properties: as a light molecule it is a valuable tool for studying dynamic biological processes. Therefore, it is a key discovery in medical and biological investigation. It is a high degree protein temporal controller, as it is able to interact in a few minutes or even seconds with molecules such as LIMK1. Its reversibility enables it to quickly activate and inhibit itself, making the molecule a specific inhibitor both ''in vitro'' and ''in cellulo''. Pyr1 can be described as a tetracyclic molecule with a simple structure. Its few radicals are widely expanded along the

benzene Benzene is an organic chemical compound with the molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar ring with one hydrogen atom attached to each. Because it contains only carbon and hydrogen atoms, ...

rings, distinguishing a benzoyloxy group in the ninth carbon and two

methyl 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 ...

radicals in carbon five and eleven. There is also a

ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bo ...

group in carbon one and two hydrogen radicals in carbons two and six.

Mechanism of action

Pyr 1 is a cell permeable competitive inhibitor of Lim Kinase (especially LIMK1). The latter is the enzyme that uses ATP to phosphorylate and inactivate the actin-depolymerizing factor cofilin. When cofilin is phosphorylated, it regulates actin dynamics. LIMK1 also depolymerizes microtubules. ESQUEMA1

In the presence of Pyr1, LIMK1 is inhibited, which means that the

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 cofilin decreases, which results in the blockage of the regulation of actin microfilaments dynamics and, therefore, the disorganization of microfilaments. It also causes the stabilization of microtubules. This inhibition is reversible. In conclusion, Pyr1 inhibits cell motility and controls actin dynamics and stabilizes microtubules. These properties can be used in anticancer treatment. ESQUEMA2

Medical applications

Cancer metastasis consists in the fast and uncontrolled division of abnormal cells. Microtubules have a key role in

mitosis In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is mainta ...

: they generate the mitotic spindle assembly, which allows

chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...

segregation and the cell division. Their stabilization leads to the inability of cells to reproduce or to their

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 ...

. That is why microtubule targeting agents are, nowadays, powerful anticancer drugs. It also explains why tubulin is now considered as one of the most highly validated cancer targets. These anticancer drugs have, however, some limitations due to side effects, principally myelosuppression and neurotoxicity. But the main inconvenience is that many cancers are, or become, resistant to these drugs. Several strategies have been proposed for the development of more effective and less toxic anticancer drugs. One of them is to use molecules that can induce the stabilization of microtubules, and Pyr1 is one of them. Pyr1 may be used in cancer treatment, because its main target enzyme (LIM kinase) is a regulator of microtubule and actin dynamics. Moreover, it has been shown that Pyr1 is toxic for cancerous cell lines, even the ones that are resistant to conventional microtubule targeting agents. Furthermore, the toxicity of Pyr1 has been studied in mice, to evaluate whether it could really work as a chemotherapeutic agent. The results show a complete survival of mice against xenografted tumors with no apparent toxicity, as there was no loss of weight observed. Therefore, it has been concluded that Pyr1 has a good therapeutic efficacy preventing tumor growth at doses that are well tolerated by animals. Bearing the previous points in mind, Pyr1 may be used in addition or as an alternative to standard chemotherapy in drug resistant tumors.

References

{{Reflist

External links

Itinéraire d’une petite molécule aux propriétés anticancéreuses prometteuses
Carbazoles Isoquinolines Heterocyclic compounds with 4 rings Benzoate esters