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D‐1553 is a small molecule inhibitor selectively targeting KRASG12C 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 KRASG12C mutation were determined by thermal shift assay and KRASG12C‐coupled nucleotide exchange assay. In vitro and in vivo antitumor activity of D‐1553 alone or in combination with other therapies were evaluated in KRASG12C mutated cancer cells and xenograft models. D‐1553 showed selective and potent activity against mutated GDP‐bound KRASG12C protein. D‐1553 selectively inhibited ERK phosphorylation in NCI‐H358 cells harboring KRASG12C mutation. Compared to the KRAS WT and KRASG12D cell lines, D‐1553 selectively inhibited cell viability in multiple KRASG12C 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 KRASG12C mutation. [ABSTRACT FROM AUTHOR]

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.)