Tomoyoshi Imaizumi, Itsuro Shimada, Yoshiki Satake, Susumu Yamaki, Takanori Koike, Takahiro Nigawara, Osamu Kaneko, Yasushi Amano, Kenichi Mori, Yosuke Yamanaka, Ayako Nakayama, Yoshihiro Nishizono, Masashi Shimazaki, Takeyuki Nagashima, Kazuyuki Kuramoto,
Bioorganic & Medicinal Chemistry, 2023, 117581
https://doi.org/10.1016/j.bmc.2023.117581.
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.
Keywords: KRAS G12C mutation; non-small cell lung cancer; structure-based drug design; hydrophobic pocket; steric hindrance; oral activity
