Article
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.
Bioorganic & medicinal chemistry - 15 Jan 2024
Imaizumi Tomoyoshi, Shimada Itsuro, Satake Yoshiki, Yamaki Susumu, Koike Takanori, Nigawara Takahiro, Kaneko Osamu, Amano Yasushi, Mori Kenichi, Yamanaka Yosuke, Nakayama Ayako, Nishizono Yoshihiro, Shimazaki Masashi, Nagashima Takeyuki, Kuramoto Kazuyuki
Abstract excerpt
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...
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