5V9O

KRAS G12C inhibitor

5V9O の概要

• エントリーDOI: 10.2210/pdb5v9o/pdb
• 関連するPDBエントリー: 5V9L
• 分子名称: GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: kras mutant inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cell membrane ; Lipid-anchor ; Cytoplasmic side : P01116
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 20274.30

構造登録者

Westover, K.,Lu, J. (登録日: 2017-03-23, 公開日: 2017-08-23, 最終更新日: 2024-10-30)

主引用文献

Zeng, M.,Lu, J.,Li, L.,Feru, F.,Quan, C.,Gero, T.W.,Ficarro, S.B.,Xiong, Y.,Ambrogio, C.,Paranal, R.M.,Catalano, M.,Shao, J.,Wong, K.K.,Marto, J.A.,Fischer, E.S.,Janne, P.A.,Scott, D.A.,Westover, K.D.,Gray, N.S.
Potent and Selective Covalent Quinazoline Inhibitors of KRAS G12C.
Cell Chem Biol, 24:1005-1016.e3, 2017

PubMed Abstract: Targeted covalent small molecules have shown promise for cancers driven by KRAS G12C. Allosteric compounds that access an inducible pocket formed by movement of a dynamic structural element in KRAS, switch II, have been reported, but these compounds require further optimization to enable their advancement into clinical development. We demonstrate that covalent quinazoline-based switch II pocket (SIIP) compounds effectively suppress GTP loading of KRAS G12C, MAPK phosphorylation, and the growth of cancer cells harboring G12C. Notably we find that adding an amide substituent to the quinazoline scaffold allows additional interactions with KRAS G12C, and remarkably increases the labeling efficiency, potency, and selectivity of KRAS G12C inhibitors. Structural studies using X-ray crystallography reveal a new conformation of SIIP and key interactions made by substituents located at the quinazoline 2-, 4-, and 7-positions. Optimized lead compounds in the quinazoline series selectively inhibit KRAS G12C-dependent signaling and cancer cell growth at sub-micromolar concentrations.

PubMed: 28781124
DOI: 10.1016/j.chembiol.2017.06.017

実験手法

X-RAY DIFFRACTION (1.56 Å)