6T5B

KRasG12C ligand complex

6T5B の概要

• エントリーDOI: 10.2210/pdb6t5b/pdb
• 分子名称: GTPase KRas, MAGNESIUM ION, GUANOSINE-5'-DIPHOSPHATE, ... (6 entities in total)
• 機能のキーワード: gtpase, signaling protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 20431.31

構造登録者

Phillips, C. (登録日: 2019-10-15, 公開日: 2020-02-26, 最終更新日: 2024-11-13)

主引用文献

Kettle, J.G.,Bagal, S.K.,Bickerton, S.,Bodnarchuk, M.S.,Breed, J.,Carbajo, R.J.,Cassar, D.J.,Chakraborty, A.,Cosulich, S.,Cumming, I.,Davies, M.,Eatherton, A.,Evans, L.,Feron, L.,Fillery, S.,Gleave, E.S.,Goldberg, F.W.,Harlfinger, S.,Hanson, L.,Howard, M.,Howells, R.,Jackson, A.,Kemmitt, P.,Kingston, J.K.,Lamont, S.,Lewis, H.J.,Li, S.,Liu, L.,Ogg, D.,Phillips, C.,Polanski, R.,Robb, G.,Robinson, D.,Ross, S.,Smith, J.M.,Tonge, M.,Whiteley, R.,Yang, J.,Zhang, L.,Zhao, X.
Structure-Based Design and Pharmacokinetic Optimization of Covalent Allosteric Inhibitors of the Mutant GTPase KRASG12C.
J.Med.Chem., 63:4468-4483, 2020

PubMed Abstract: Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRAS mutant represents an "Achilles heel" and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket on GDP-bound RAS, locking it in an inactive state. A weak inhibitor at this site was optimized through conformational locking of a piperazine-quinazoline motif and linker modification. Subsequent introduction of a key methyl group to the piperazine resulted in enhancements in potency, permeability, clearance, and reactivity, leading to identification of a potent KRAS inhibitor with high selectivity and excellent cross-species pharmacokinetic parameters and in vivo efficacy.

PubMed: 32023060
DOI: 10.1021/acs.jmedchem.9b01720

実験手法

X-RAY DIFFRACTION (1.37 Å)