6usx

Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer

spinqualitylabelsall models 6usx, resolution 2.27Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.27Å Ligands: GDP, M1R, MG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Capping off an era marred by drug development failures and punctuated by waning interest and presumed intractability toward direct targeting of KRAS, new technologies and strategies are aiding in the target's resurgence. As previously reported, the tetrahydropyridopyrimidines were identified as irreversible covalent inhibitors of KRAS(G12C) that bind in the switch-II pocket of KRAS and make a covalent bond to cysteine 12. Using structure-based drug design in conjunction with a focused in vitro absorption, distribution, metabolism and excretion screening approach, analogues were synthesized to increase the potency and reduce metabolic liabilities of this series. The discovery of the clinical development candidate MRTX849 as a potent, selective covalent inhibitor of KRAS(G12C) is described. Identification of the Clinical Development Candidate MRTX849, a Covalent KRAS(G12C) Inhibitor for the Treatment of Cancer.,Fell JB, Fischer JP, Baer BR, Blake JF, Bouhana K, Briere DM, Brown KD, Burgess LE, Burns AC, Burkard MR, Chiang H, Chicarelli MJ, Cook AW, Gaudino JJ, Hallin J, Hanson L, Hartley DP, Hicken EJ, Hingorani GP, Hinklin RJ, Mejia MJ, Olson P, Otten JN, Rhodes SP, Rodriguez ME, Savechenkov P, Smith DJ, Sudhakar N, Sullivan FX, Tang TP, Vigers GP, Wollenberg L, Christensen JG, Marx MA J Med Chem. 2020 Apr 6. doi: 10.1021/acs.jmedchem.9b02052. PMID:32250617 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also GTPase KRas 3D structures

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