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.