9C1R

Crystal structure of mutant cMET D1228N kinase domain in complex with inhibitor compound 13

This is a non-PDB format compatible entry.

Summary for 9C1R

• Entry DOI: 10.2210/pdb9c1r/pdb
• Descriptor: Hepatocyte growth factor receptor, GLYCEROL, N-(2,5-difluoro-4-{[(1s,3S)-3-(1-methyl-1H-pyrazol-3-yl)cyclobutyl][(8R)-pyrazolo[1,5-a]pyrazin-4-yl]amino}phenyl)-2-(5-fluoropyridin-2-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide, ... (4 entities in total)
• Functional Keywords: cmet kinase domain, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 35650.13

Authors

Simpson, H.,Wu, W.-I.,Mou, T.-C. (deposition date: 2024-05-29, release date: 2024-08-21, Last modification date: 2024-09-04)

Primary citation

Bumpers, Q.A.,Pipal, R.W.,Benz-Weeden, A.M.,Brewster 2nd, J.T.,Cook, A.,Crooks, A.L.,Cruz, C.,Dwulet, N.C.,Gaudino, J.J.,Golec, D.,Harrison, J.A.,Hartley, D.P.,Hassanien, S.H.,Hicken, E.J.,Kahn, D.,Laird, E.R.,Lemieux, C.,Lewandowski, N.,McCown, J.,McDonald, M.G.,McNulty, O.,Mou, T.C.,Nguyen, P.,Oko, L.,Opie, L.P.,Otten, J.,Peck, S.C.,Polites, V.C.,Randall, S.D.,Rosen, R.Z.,Savechenkov, P.,Simpson, H.,Singh, A.,Sparks, D.,Wickersham, K.,Wollenberg, L.,Wong, C.E.,Wong, J.,Wu, W.I.,Elsayed, M.S.A.,Hinklin, R.J.,Tang, T.P.
Discovery of Pyrazolopyrazines as Selective, Potent, and Mutant-Active MET Inhibitors with Intracranial Efficacy.
J.Med.Chem., 67:14466-14477, 2024

PubMed Abstract: Mesenchymal-epithelial transition factor (MET) is a receptor tyrosine kinase that serves a critical function in numerous developmental, morphogenic, and proliferative signaling pathways. If dysregulated, MET has been shown to be involved in the development and survival of several cancers, including non-small cell lung cancer (NSCLC), renal cancer, and other epithelial tumors. Currently, the clinical efficacy of FDA approved MET inhibitors is limited by on-target acquired resistance, dose-limiting toxicities, and less than optimal efficacy against brain metastasis. Therefore, there is still an unmet medical need for the development of MET inhibitors to address these issues. Herein we report the application of structure-based design for the discovery and development of a novel class of brain-penetrant MET inhibitors with enhanced activity against clinically relevant mutations and improved selectivity. Compound with a MET D1228N cell line IC value of 23 nM showed good efficacy in an intracranial tumor model and increased the median overall survival of the animals to 100% when dosed orally at 100 mg/kg daily for 21 days.

PubMed: 39088797
DOI: 10.1021/acs.jmedchem.4c01232

Experimental method

X-RAY DIFFRACTION (1.59 Å)