Abstract 2681: Novel and selective inhibitors of KRASG12D

Abstract

Abstract RAS proteins are family of small GTP-binding proteins that play a major role in regulating cellular responses such as proliferation, differentiation, migration, and cell growth. RAS proteins function as molecular switches, cycling between inactive (GDP-bound) and active (GTP-bound) states, which relay cellular signals in response to extracellular stimuli. Aberrant RAS signaling plays a role in up to 30% of all human cancers, with the highest incidence occurring in carcinomas of the pancreas (63–90%), colon (36–50%), and lung (19–30%). Targeting the inactive, GDP bound KRASG12C has been a promising approach for generating novel anti RAS therapies, which is validated by the approval of AMG 510 (Lumakras) by the FDA. It is also known that KRASG12D also retains GTPase activity. Consequently, KRASG12D is one of the most important chemotherapeutic drug targets. KRASG12D is commonly observed in pancreatic cancer. Here we describe preclinical profile of a potent, selective, in-vivo tool compound, VRTX144. VRTX144 was potent in HPAC cell line, representing pancreatic adenocarcinoma, and a panel of KRASG12D mutated cell lines. It was found to be several folds less active in non-KRASG12D mutant cell lines. In vitro combination strategies with other targeted therapies such as EGFR, SHP2 and CDK4/6 inhibitor is also being investigated. VRTX144 exhibited low propensity for metabolism in microsomes, and has high protein bound. VRTX144 was found to have no adverse effect in hERG upto 10 uM. Citation Format: Prashant Kashinath Bhavar, Uday Kumar Surampudi, Partha Pratim Sarma, Mahesh Mohan Shidore, Anuj Ramesh Kshirsagar. Novel and selective inhibitors of KRASG12D [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2681.