7TLG

Crystal Structure of small molecule beta-lactone 5 covalently bound to K-Ras(G12S)

7TLG の概要

• エントリーDOI: 10.2210/pdb7tlg/pdb
• 分子名称: GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, (3R,4R)-1-[7-(8-chloronaphthalen-1-yl)-8-fluoro-2-{[(4S,7as)-tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-3-hydroxypiperidine-4-carbaldehyde, ... (5 entities in total)
• 機能のキーワード: ras, oncoprotein
• 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: 40760.58

構造登録者

Ziyang, Z.,Guiley, K.Z.,Shokat, K.M. (登録日: 2022-01-18, 公開日: 2022-08-03, 最終更新日: 2024-10-09)

主引用文献

Zhang, Z.,Guiley, K.Z.,Shokat, K.M.
Chemical acylation of an acquired serine suppresses oncogenic signaling of K-Ras(G12S).
Nat.Chem.Biol., 18:1177-1183, 2022

PubMed Abstract: Drugs that directly impede the function of driver oncogenes offer exceptional efficacy and a therapeutic window. The recently approved mutant selective small-molecule cysteine-reactive covalent inhibitor of the G12C mutant of K-Ras, sotorasib, provides a case in point. KRAS is the most frequently mutated proto-oncogene in human cancer, yet despite success targeting the G12C allele, targeted therapy for other hotspot mutants of KRAS has not been described. Here we report the discovery of small molecules that covalently target a G12S somatic mutation in K-Ras and suppress its oncogenic signaling. We show that these molecules are active in cells expressing K-Ras(G12S) but spare the wild-type protein. Our results provide a path to targeting a second somatic mutation in the oncogene KRAS by overcoming the weak nucleophilicity of an acquired serine residue. The chemistry we describe may serve as a basis for the selective targeting of other unactivated serines.

PubMed: 35864332
DOI: 10.1038/s41589-022-01065-9

実験手法

X-RAY DIFFRACTION (1.80000720583 Å)