9IB4

Structure of 12 in complex with GDP-KRAS

これはPDB形式変換不可エントリーです。

9IB4 の概要

• エントリーDOI: 10.2210/pdb9ib4/pdb
• 関連するPDBエントリー: 9IAP 9IAW 9IAY
• 分子名称: GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (6 entities in total)
• 機能のキーワード: kras, ras-like p-loop gtpases, inhibitor, hydrolase
• 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: 20355.93

構造登録者

Boettcher, J. (登録日: 2025-02-11, 公開日: 2025-08-06, 最終更新日: 2025-08-27)

主引用文献

Broker, J.,Waterson, A.G.,Hodges, T.R.,Abbott, J.R.,Arnold, A.,Bottcher, J.,Braun, N.,Cui, J.,Fuchs, J.E.,Gerstberger, T.,Gogg, S.,Hanner, S.,Herdeis, L.,Howell, L.W.,Mantoulidis, A.,Mayer, M.,Phan, J.,Rocchetti, F.,Sankar, K.,Sarkar, D.,Schaaf, O.,Sensintaffar, J.L.,Sun, Q.,Wunberg, T.,Fesik, S.W.
Discovery of BI-2493, a Pan-KRAS Inhibitor Showing In Vivo Efficacy.
J.Med.Chem., 68:15649-15668, 2025

PubMed Abstract: KRAS is one of the most highly validated cancer targets. Here we describe the design and synthesis of two reversible pan-KRAS inhibitors, BI-2865 and BI-2493. From our KRAS inhibitor program, we identified BI-2865, a potent noncovalent KRAS inhibitor that showed cellular activity against a broad spectrum of KRAS alleles and selectivity against HRAS and NRAS. Spirocyclization led to the discovery of BI-2493, a highly rigid analogue exhibiting better potency, metabolic stability, and permeability. BI-2493 shows efficacy in various KRAS mutant and KRAS wild-type amplified xenograft models and represents a promising starting point for further optimization.

PubMed: 40709733
DOI: 10.1021/acs.jmedchem.5c00576

実験手法

X-RAY DIFFRACTION (1.062 Å)