9U50

GDP-bound KRAS G12V in complex with MCB-294

This is a non-PDB format compatible entry.

Summary for 9U50

• Entry DOI: 10.2210/pdb9u50/pdb
• Descriptor: Isoform 2B of GTPase KRas, MAGNESIUM ION, (3~{R})-1-[2-[[(8~{S})-6-[bis(fluoranyl)methylidene]-2,3,5,7-tetrahydro-1~{H}-pyrrolizin-8-yl]methoxy]-7-(8-ethynyl-7-fluoranyl-3-oxidanyl-naphthalen-1-yl)-8-fluoranyl-pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol, ... (5 entities in total)
• Functional Keywords: gdp-bound, inhibitor, oncoprotein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 3
• Total formula weight: 62398.11

Authors

Li, K.K.,Guo, R.-T. (deposition date: 2025-03-20, release date: 2025-07-30, Last modification date: 2025-10-29)

Primary citation

Feng, J.,Xiao, X.,Xia, X.,Min, J.,Tang, W.,Shi, X.,Xu, K.,Zhou, G.,Li, K.,Shen, P.,Bao, R.,Wu, S.,Lin, M.,Yuan, K.,Lian, Z.,Hu, L.,Li, N.,Wu, Z.,Zhai, X.,Liu, X.,Hu, K.,Wu, J.,Ding, C.,Zhao, H.,Gong, X.,Zhang, S.,Jin, J.,Li, D.,Liu, M.,Ye, Y.,Ma, B.,Guo, R.T.,Zhang, A.,Pang, X.
A pan-KRAS inhibitor and its derived degrader elicit multifaceted anti-tumor efficacy in KRAS-driven cancers.
Cancer Cell, 43:1866-, 2025

PubMed Abstract: KRAS remains a challenging therapeutic target with limited effective inhibitors currently available. Here, we report the discovery of MCB-294, a potent dual-state pan-KRAS inhibitor capable of binding both the active (GTP-bound) and inactive (GDP-bound) forms of KRAS. MCB-294 engages the switch-II pocket through a water-mediated hydrogen-bond network and selectively inhibits KRAS over NRAS and HRAS. It effectively suppresses oncogenic KRAS signaling, inhibits the growth of KRAS-dependent cancer cells and patient-derived organoids, and reduces tumor progression in multiple preclinical models. MCB-294 also demonstrates superior activity compared to the inactive-state selective pan-KRAS inhibitor Bl-2865 and the KRAS inhibitor MRTX1133. Building upon MCB-294 as a pan-KRAS-targeting warhead, we further develop MCB-36, a von Hippel-Lindau (VHL)-recruiting pan-KRAS degrader that induces sustained KRAS degradation. Notably, both MCB-294 and MCB-36 effectively suppress KRAS inhibitor-resistant cancer cells and remodel the tumor immune microenvironment. These findings highlight a promising therapeutic strategy for broadly targeting KRAS-driven tumors and overcoming drug resistance.

PubMed: 40780213
DOI: 10.1016/j.ccell.2025.07.006

Experimental method

X-RAY DIFFRACTION (1.87 Å)