9E5D

Discovery of an Orally Biovailable KRAS G12D Inhibitor

これはPDB形式変換不可エントリーです。

9E5D の概要

• エントリーDOI: 10.2210/pdb9e5d/pdb
• 分子名称: GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: inhibitor, oncoprotein, gtpase, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase 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: 20502.10

構造登録者

Deller, M.C.,Epling, L.B. (登録日: 2024-10-28, 公開日: 2025-01-22, 最終更新日: 2025-02-05)

主引用文献

Ye, Q.,Shvartsbart, A.,Li, Z.,Gan, P.,Policarpo, R.L.,Qi, C.,Roach, J.J.,Zhu, W.,McCammant, M.S.,Hu, B.,Li, G.,Yin, H.,Carlsen, P.,Hoang, G.,Zhao, L.,Susick, R.,Zhang, F.,Lai, C.T.,Allali Hassani, A.,Epling, L.B.,Gallion, A.,Kurzeja-Lipinski, K.,Gallagher, K.,Roman, V.,Farren, M.R.,Kong, W.,Deller, M.C.,Zhang, G.,Covington, M.,Diamond, S.,Kim, S.,Yao, W.,Sokolsky, A.,Wang, X.
Discovery of INCB159020, an Orally Bioavailable KRAS G12D Inhibitor.
J.Med.Chem., 68:1924-1939, 2025

PubMed Abstract: The inhibition of mutant KRAS proteins has emerged as a promising approach for treating KRAS-driven cancers, as evidenced by the clinical success of KRAS G12C inhibitors. KRAS G12D, the most common mutant, promises significant expansion of the addressable patient population; however, the reduced nucleophilicity of aspartate compared to cysteine poses significant challenges in balancing sufficient potency with ADME properties to support oral exposure. Herein, we describe the discovery of KRAS G12D inhibitor (), which achieves oral exposure in nonhuman primate (NHP). Starting from a weakly potent hit, structure-based drug design was utilized to drive significant potency. Focus on molecular rigidity and balanced polarity then allowed for successful optimization of properties required for oral exposure.

PubMed: 39772605
DOI: 10.1021/acs.jmedchem.4c02662

実験手法

X-RAY DIFFRACTION (1.36 Å)