Abstract C081: Novel and selective inhibitors of KRASG12V

Abstract

KRAS is one the most mutated proteins in cancers and are commonly identified in pancreatic adenocarcinoma, colorectal and non-small cell lung cancer. Owing to its role in a different human cancer, KRAS has long been considered as an important therapeutic target in precision oncology. Although KRAS was considered undruggable due to the protein’s structural complexity, recent allele specific inhibitors that covalently bind and trap KRAS in its inactive GDP bound state have demonstrated promising approach for generating anti RAS therapies and is validated by the accelerated approval of Sotorasib and Adagrasib by the FDA for patients with lung cancer. Success of targeting mutant KRASG12C has opened opportunities to tackle other oncogenic KRAS variants such as KRASG12V.  KRASG12V mutations occur frequently in multiple tumour histotypes such as adenocarcinoma of Pancreas (~32%), colorectal adenocarcinoma (~20%) and Lung (~19%) and represents a significant unmet medical need.  Here we describe preclinical profile of a potent and selective KRASG12V inhibitor VRTX171. VRTX171 is a tool compound that was potent across a KRASG12V mutated cancer cell line and found to be several fold less active in non-KRASG12V mutant cell lines.  Using a de novo drug design approach the compound was optimized to offer desired potency with high selectivity over WT KRAS and other KRAS mutant isoforms. Affinity for target protein, was assessed by HTRF based target engagement assay and inhibition of Raf/Mitogen-activated protein kinase (MAPK) pathway was determined using Western blot analysis in multiple cancer cell lines harbouring KRASG12V mutation. In-vivo studies of VRTX171 in Xenograft models harbouring KRASG12V mutations, as single agent as well as in combination with other targeted therapies are under consideration.

Citation Format: Prashant Kashinath Bhavar, Uday Kumar Surampudi. Novel and selective inhibitors of KRASG12V [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C081.