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C-Met Library

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ChemDiv's C-Met library contains 16,000 compounds.

Receptor tyrosine kinases (RTKs) regulate many essential cellular processes in mammalian development, cell function and tissue homeostasis. The protein product of c-MET proto-oncogene is the c-MET tyrosine kinase. This cell surface receptor is expressed in epithelial cells of many organs, including the liver, pancreas, prostate, kidney, muscle and bone marrow, during both embryogenesis and adulthood. C-MET ligand is hepatocyte growth factor (HGF), it acts as a pleiotropic factor and cytokine, promoting cell proliferation, survival, motility, scattering, differentiation and morphogenesis. Binding c-MET and HGF can lead to activation of other signaling pathways such as PI3K and mTOR. Since RTKs are important in normal physiology, the dysregulation of certain RTKs has been implicated in the development and progression of many types of cancer. Expression of the c-MET and HGF has been detected in tumor biopsies of most solid tumors and c-MET signaling has been found in a wide range of human malignancies. [1]

The majority of the compounds in development target directly the receptor. Small molecule inhibitors can act in an ATP-competitive or non-competitive fashion. ATP-competitive inhibitors are very potent but less specific because they can inhibit other kinases. The non-competitive inhibitors could be more specific since they are not in general directly interacting with the ATP pocket but rather with allosteric sites of the receptor, which are not shared by other kinases. Binding to the allosteric sites leads to changes in the conformation of the active site, which alters the binding of the ligand HGF.  The example of ATP-competitive drug is cabozantinib, which successfully inhibits MET and shows antitumor activity. [2]

[1]         S. L. Organ and M. S. Tsao, “An overview of the c-MET signaling pathway,” Therapeutic Advances in Medical Oncology, vol. 3, no. 1. SAGE Publications, pp. S7–S19, 2011, doi: 10.1177/1758834011422556.

[2]         A. Fasolo, C. Sessa, L. Gianni, and M. Broggini, “Seminars in clinical pharmacology: An introduction to met inhibitors for the medical oncologist,” Ann. Oncol., vol. 24, no. 1, pp. 14–20, 2013, doi: 10.1093/annonc/mds520.

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