Discovery of novel coumarin-based KRAS-G12C inhibitors from virtual screening and Rational structural optimization

KRAS-G12C inhibitors has been made significant progress in the treatment of KRAS-G12C mutant cancers, but their clinical application is limited due to the adaptive resistance, motivating development of novel structural inhibitors. Herein, series of coumarin derivatives as KRAS-G12C inhibitors were found through virtual screening and rational structural optimization. Especially, K45 exhibited strong antiproliferative potency on NCI-H23 and NCI-H358 Cancer cells harboring KRAS-G12C with the IC₅₀ values of 0.77 μM and 1.50 μM, which was 15 and 11 times as potent as positive drug ARS1620, respectively. Furthermore, K45 reduced the phosphorylation of KRAS downstream effectors ERK and Akt by reducing the active form of KRAS (KRAS GTP) in NCI-H23 cells. In addition, K45 induced cell Apoptosis by increasing the expression of anti-apoptotic protein BAD and Bax in NCI-H23 cells. Docking studies displayed that the 3-naphthylmethoxy moiety of K45 extended into the cryptic pocket formed by the residues Gln99 and Val9, which enhanced the interaction with the KRAS-G12C protein. These results indicated that K45 was a potent KRAS-G12C inhibitor worthy of further study.

Antiproliferative effect; Coumarin; KRAS-G12C; SARs.