9E5F

Discovery of an Orally Bioavailable KRAS G12D Inhibitor

This is a non-PDB format compatible entry.

Summary for 9E5F

• Entry DOI: 10.2210/pdb9e5f/pdb
• Related: 9E5D
• Descriptor: GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, (4P)-4-{1-[(1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl]-8-chloro-4-[3-(dimethylamino)azetidin-1-yl]-6-fluoro-1H-imidazo[4,5-c]quinolin-7-yl}naphthalen-2-ol, ... (5 entities in total)
• Functional Keywords: inhibitor, oncoprotein, gtpase, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 20397.39

Authors

Deller, M.C.,Epling, L.B. (deposition date: 2024-10-28, release date: 2025-01-22, Last modification date: 2025-02-05)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.35 Å)