Cogent Biosciences announces pipeline expansion into KRAS

Cogent Biosciences (COGT) announced the addition of a potent and selective KRAS inhibitor to its pipeline. Preclinical data from this program as well as its newly announced H1047R mutant-selective PI3Kalpha clinical candidate will be presented in two poster presentations at the 2024 EORTC-NCI-AACR International Symposium on Molecular Targets and Cancer Therapeutics taking place in Barcelona, Spain October 23-25, 2024. Title: Identification of a Pan KRAS(On) Inhibitor with Selectivity Over KRAS over H/NRAS and pM Activity Across Prevalent KRAS Mutations: Mutations in KRAS are among the most prevalent mutations found in cancer, occurring most often in colorectal cancer, non-small cell lung cancer and pancreatic cancer. The poster presented today describes Cogent’s internally-developed pan KRAS(ON) inhibitor with selectivity over HRAS and NRAS and picomolar activity across KRAS mutations without the potential liabilities of molecules in the class. Following oral administration, CGT6737 demonstrated robust PK/PD and tumor growth inhibition with 90% PD inhibition in mouse xenograft models. Lead optimization of CGT6737 is ongoing. Title: Preclinical Characterization of a Novel PI3Kalpha H1047R Mutant Selective Inhibitor: Cogent is also developing a potential best-in-class, wild-type-sparing, PI3Kalpha inhibitor that provides coverage for the H1047R mutation, which affects greater than55,000 cancer patients each year. The phosphoinositide 3-kinase pathway is a key cell cycle regulating pathway that has an established role in tumor growth and development. The approved agents for these patients often lead to dose limitations, resulting from activity against wild-type PI3Kalpha. The poster presented today highlights Cogent’s clinical candidate CGT6297, a potent allosteric inhibitor of PI3K, with 25-fold selectivity over PI3Kalpha WT. CGT6297 has high oral bioavailability and low clearance across species, providing robust inhibition of downstream signaling and efficacy in animal models. Importantly, when compared to a clinically relevant dose of a currently approved therapy in a mouse tumor model, CGT6297 demonstrated superior efficacy with no increase in insulin. IND-enabling studies are expected to be initiated in 2025.