D-1553: A novel KRAS G12C inhibitor with potent and selective cellular and in vivo antitumor activity.

D-1553 is a small molecule inhibitor selectively targeting KRAS ^G12C and currently in phase II clinical trials. Here, we report the preclinical data demonstrating antitumor activity of D-1553. Potency and specificity of D-1553 in inhibiting GDP-bound KRAS ^G12C mutation were determined by thermal shift assay and KRAS ^G12C -coupled nucleotide exchange assay. In vitro and in vivo antitumor activity of D-1553 alone or in combination with other therapies were evaluated in KRAS ^G12C mutated cancer cells and xenograft models. D-1553 showed selective and potent activity against mutated GDP-bound KRAS ^G12C protein. D-1553 selectively inhibited ERK phosphorylation in NCI-H358 cells harboring KRAS ^G12C mutation. Compared to the KRAS WT and KRAS ^G12D cell lines, D-1553 selectively inhibited cell viability in multiple KRAS ^G12C cell lines, and the potency was slightly superior to sotorasib and adagrasib. In a panel of xenograft tumor models, D-1553, given orally, showed partial or complete tumor regression. The combination of D-1553 with chemotherapy, MEK inhibitor, or SHP2 inhibitor showed stronger potency on tumor growth inhibition or regression compared to D-1553 alone. These findings support the clinical evaluation of D-1553 as an efficacious drug candidate, both as a single agent or in combination, for patients with solid tumors harboring KRAS ^G12C mutation.
(© 2023 InventisBio Co., Ltd and The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)