6USX

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

6USX の概要

• エントリーDOI: 10.2210/pdb6usx/pdb
• 分子名称: GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: hydrolase inhibitor, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 40669.91

構造登録者

Vigers, G.P.,Smith, D.J. (登録日: 2019-10-28, 公開日: 2020-04-22, 最終更新日: 2024-10-23)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.27 Å)