9E9H

Crystal structure of human KRAS G12C covalently bound to DEL triazine compound 5

これはPDB形式変換不可エントリーです。

9E9H の概要

• エントリーDOI: 10.2210/pdb9e9h/pdb
• 分子名称: GTPase KRas, CALCIUM ION, GUANOSINE-5'-DIPHOSPHATE, ... (5 entities in total)
• 機能のキーワード: inhibitor, gtpase, signaling protein, oncoprotein-inhibitor complex, oncoprotein/inhibitor
• 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: 22086.61

構造登録者

Mohr, C. (登録日: 2024-11-08, 公開日: 2025-02-26, 最終更新日: 2025-03-05)

主引用文献

Huang, D.,Manoni, F.,Sun, Z.,Liu, R.,Allen, J.R.,Banerjee, A.,Cee, V.J.,Eshon, J.,Frohn, M.J.,Kaller, M.R.,Lee, H.,Li, C.,Li, X.,Lopez, P.,Ma, V.,Medina, J.M.,Mohr, C.,Mukhina, O.A.,Pickrell, A.J.,Stellwagen, J.,Wu, W.,Zhang, W.,Zhu, K.,Dahal, U.P.,Hu, L.A.,Leavitt, M.,Li, W.,Li, Y.,Ma, Y.,Rex, K.,Saiki, A.Y.,Wang, P.,Sun, Y.,Dai, D.,Tamayo, N.A.,Lanman, B.A.
Identification of Structurally Novel KRAS G12C Inhibitors through Covalent DNA-Encoded Library Screening.
J.Med.Chem., 68:4801-4817, 2025

PubMed Abstract: Covalent inhibition of the KRAS oncoprotein has emerged as a promising therapeutic approach for the treatment of nonsmall cell lung cancer (NSCLC). The identification of KRAS inhibitors has typically relied on the high-throughput screening (HTS) of libraries of cysteine-reactive small molecules or on the attachment of cysteine-reactive warheads to noncovalent binders of KRAS. Such screening approaches have historically been limited in the size and diversity of molecules that could be effectively screened. DNA-encoded library (DEL) screening has emerged as a promising approach to accelerate the preparation and screening of incredibly large and diverse chemical libraries. Here, we describe the design and synthesis of a covalent DEL to screen ∼16 million compounds against KRAS. We additionally describe the hit identification, validation, and structure-based optimization that culminated in the identification of a series of structurally novel, potent, and selective covalent inhibitors of KRAS with good pharmacokinetic profiles and promising in vivo pharmacodynamic effects.

PubMed: 39930787
DOI: 10.1021/acs.jmedchem.4c03071

実験手法

X-RAY DIFFRACTION (1.65 Å)