Abstract 4481: Vrtx153, novel small molecule inhibitor of krasg12d

Abstract Pancreatic cancer is an intractable malignancy and is the seventh leading cause of global cancer deaths in industrialized countries and the third most common in the USA. Despite advancement in the knowledge of potential risk factors that cause pancreatic cancer and newly available tools for early diagnosis, its incidence is estimated to increase and will include 0.35 mln new cases within 2040. KRAS is the predominant isoform mutated in cancer and are found in 92-95% of Pancreatic Cancer patients, dominated by somatic mutations of KRASG12D. KRASG12D, is one of the most frequently mutated oncogenes across adenocarcinoma of Pancreas (51%), Colon and Rectal (13.4%) and Lung (3%). With KRAS mutations found in nearly all PDAC, this cancer type is arguably the most RAS-addicted cancer. KRASG12D is a clinically relevant target but owing to structural complexity of the protein, poses challenges for its effective inhibition. Previously, we reported a series of compound including a proprietary tool compound VTRX144, with low nM potency in 2D (<25 nM). Optimized lead from VRise de-novo platform has yielded an unparallel potent, highly selective, inhibitor, namely VRTX153. VRTX153 demonstrated high-affinity for KRASG12D in a GDP-loaded KRASG12D assay, with an IC50 value of less than 2 nM and more than1500 -fold selectivity over KRASWT, KRAS mutants and other RAS proteins including HRAS & NRAS. VRTX153 inhibited ERK1/2 phosphorylation (pERK) and cell viability in KRASG12D-mutant cell lines in both 2D and 3D, as evaluated by CellTiter-Glo®. In-vivo translation of activity in a mouse xenograft model representing PDAC is being investigated. Citation Format: Prashant Kashinath Bhavar, Uday Kumar Surampudi, Partha Pratim Sarma, Anuj Ramesh Kshirsagar. Vrtx153, novel small molecule inhibitor of krasg12d. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4481.