8X6R

KRasG12C in complex with inhibitor

Summary for 8X6R

• Entry DOI: 10.2210/pdb8x6r/pdb
• Descriptor: Isoform 2B of GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: gtp-binding, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 6
• Total formula weight: 122700.78

Authors

Amano, Y.,Tateishi, Y. (deposition date: 2023-11-21, release date: 2024-01-17)

Primary citation

Imaizumi, T.,Shimada, I.,Satake, Y.,Yamaki, S.,Koike, T.,Nigawara, T.,Kaneko, O.,Amano, Y.,Mori, K.,Yamanaka, Y.,Nakayama, A.,Nishizono, Y.,Shimazaki, M.,Nagashima, T.,Kuramoto, K.
Discovery of ASP6918, a KRAS G12C inhibitor: Synthesis and structure-activity relationships of 1-{2,7-diazaspiro[3.5]non-2-yl}prop-2-en-1-one derivatives as covalent inhibitors with good potency and oral activity for the treatment of solid tumors.
Bioorg.Med.Chem., 98:117581-117581, 2023

PubMed Abstract: Although KRAS protein had been classified as an undruggable target, inhibitors of KRAS G12C mutant protein were recently reported to show clinical efficacy in solid tumors. In our previous report, we identified 1-{2,7-diazaspiro[3.5]non-2-yl}prop-2-en-1-one derivative (1) as a KRAS G12C inhibitor that covalently binds to Cys12 of KRAS G12C protein. Compound 1 exhibited potent cellular pERK inhibition and cell growth inhibition against a KRAS G12C mutation-positive cell line and showed an antitumor effect on subcutaneous administration in an NCI-H1373 (KRAS G12C mutation-positive cell line) xenograft mouse model in a dose-dependent manner. In this report, we further optimized the substituents on the quinazoline scaffold based on the structure-based drug design from the co-crystal structure analysis of compound 1 and KRAS G12C to enhance in vitro activity. As a result, ASP6918 was found to exhibit extremely potent in vitro activity and induce dose-dependent tumor regression in an NCI-H1373 xenograft mouse model after oral administration.

PubMed: 38176113
DOI: 10.1016/j.bmc.2023.117581

Experimental method

X-RAY DIFFRACTION (1.85 Å)