7O83

KRasG12C ligand complex

7O83 の概要

• エントリーDOI: 10.2210/pdb7o83/pdb
• 分子名称: V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog, isoform CRA_b, MAGNESIUM ION, GUANOSINE-5'-DIPHOSPHATE, ... (6 entities in total)
• 機能のキーワード: inhibitor complex, signaling protein
• 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: 40089.93

構造登録者

Phillips, C.,Breed, J. (登録日: 2021-04-14, 公開日: 2022-04-20, 最終更新日: 2024-11-20)

主引用文献

Kettle, J.G.,Bagal, S.K.,Bickerton, S.,Bodnarchuk, M.S.,Boyd, S.,Breed, J.,Carbajo, R.J.,Cassar, D.J.,Chakraborty, A.,Cosulich, S.,Cumming, I.,Davies, M.,Davies, N.L.,Eatherton, A.,Evans, L.,Feron, L.,Fillery, S.,Gleave, E.S.,Goldberg, F.W.,Hanson, L.,Harlfinger, S.,Howard, M.,Howells, R.,Jackson, A.,Kemmitt, P.,Lamont, G.,Lamont, S.,Lewis, H.J.,Liu, L.,Niedbala, M.J.,Phillips, C.,Polanski, R.,Raubo, P.,Robb, G.,Robinson, D.M.,Ross, S.,Sanders, M.G.,Tonge, M.,Whiteley, R.,Wilkinson, S.,Yang, J.,Zhang, W.
Discovery of AZD4625, a Covalent Allosteric Inhibitor of the Mutant GTPase KRAS G12C .
J.Med.Chem., 65:6940-6952, 2022

PubMed Abstract: KRAS is an archetypal high-value intractable oncology drug target. The glycine to cysteine mutation at codon 12 represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of , AZD4625, a clinical development candidate for the treatment of KRAS positive tumors. Highlights include a quinazoline tethering strategy to lock out a bio-relevant binding conformation and an optimization strategy focused on the reduction of extrahepatic clearance mechanisms seen in preclinical species. Crystallographic analysis was also key in helping to rationalize unusual structure-activity relationship in terms of ring size and enantio-preference. AZD4625 is a highly potent and selective inhibitor of KRAS with an anticipated low clearance and high oral bioavailability profile in humans.

PubMed: 35471939
DOI: 10.1021/acs.jmedchem.2c00369

実験手法

X-RAY DIFFRACTION (2.38 Å)