6UT0

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

Summary for 6UT0

• Entry DOI: 10.2210/pdb6ut0/pdb
• Related: 6USX 6USZ
• Descriptor: GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: hydrolase inhibitor, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 81705.70

Authors

Vigers, G.P.,Smith, D.J. (deposition date: 2019-10-29, release date: 2020-04-22, Last modification date: 2024-11-13)

Primary citation

Fell, J.B.,Fischer, J.P.,Baer, B.R.,Blake, J.F.,Bouhana, K.,Briere, D.M.,Brown, K.D.,Burgess, L.E.,Burns, A.C.,Burkard, M.R.,Chiang, H.,Chicarelli, M.J.,Cook, A.W.,Gaudino, J.J.,Hallin, J.,Hanson, L.,Hartley, D.P.,Hicken, E.J.,Hingorani, G.P.,Hinklin, R.J.,Mejia, M.J.,Olson, P.,Otten, J.N.,Rhodes, S.P.,Rodriguez, M.E.,Savechenkov, P.,Smith, D.J.,Sudhakar, N.,Sullivan, F.X.,Tang, T.P.,Vigers, G.P.,Wollenberg, L.,Christensen, J.G.,Marx, M.A.
Identification of the Clinical Development CandidateMRTX849, a Covalent KRASG12CInhibitor for the Treatment of Cancer.
J.Med.Chem., 63:6679-6693, 2020

PubMed Abstract: 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 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 as a potent, selective covalent inhibitor of KRAS is described.

PubMed: 32250617
DOI: 10.1021/acs.jmedchem.9b02052

Experimental method

X-RAY DIFFRACTION (1.94 Å)