Abstract B116: Preclinical characterization of orally bioavailable, highly potent pan-KRAS inhibitors with selectivity over HRAS and NRAS
Authors: Vallejo Lourdes Prieto , Iyer Chandrasekar , Goggin Noelle , Li Binghui , Yang Peiyi , Bian Huimin , Podoll Jessica , Grotegut Stefan , Tandon Manuj , Anderson Bryan D , Capen Andrew , Xiao Min , Wang Tao , Stewart Trent R , Aronow Sean , Bume Desta , Garcia Isabel Rojo , Si Chong , Cooke Andrew , Bondi Robert , Kelamangalath Lakshmi , Wallace Ross , Kolakowski Gabrielle , LeBrun Lauire , Henry James R , Kercher Tim 
Published: December 2023

KRAS is altered in ~16% of all cancers and is an oncogenic driver in non-small cell lung, pancreatic, colorectal, and other cancers. Next generation KRAS inhibitors designed to target multiple oncogenic KRAS mutations, while simultaneously sparing wild-type (WT) HRAS and NRAS inhibition, are expected to offer expanded activity and favorable safety. We have discovered a series of highly potent and selective pan-KRAS inhibitors with activity against KRAS G12C, G12D, and G12V mutants, that also display high selectivity over WT HRAS and NRAS, thus providing an expanded therapeutic index. Here, we describe the preclinical profile of these pan-KRAS inhibitors. Compound potency and selectivity were measured using surface plasmon resonance (SPR) assays and cell-based assays measuring inhibition of p-ERK and 3D cell growth of KRAS-mutant tumor cell lines. These pan-KRAS inhibitors have IC50 values ranging from 3-14 nM for KRAS G12C, G12D, G12V, and WT KRAS in phospho-ERK cell-based assays and selectivity of &gt;200-fold over NRAS WT and &gt;100-fold over HRAS WT. These pan-KRAS inhibitors show a clean safety profile in a 133 off-target panel screen. These pan-KRAS inhibitors demonstrate favorable in vitro ADME properties and oral bioavailability in preclinical species. Tumor growth inhibition and PK/PD studies were performed in mice. In vivo, the pan-KRAS inhibitors administered orally demonstrated dose-dependent target inhibition in KRAS-mutant xenograft models. These data demonstrate that our pan-KRAS inhibitors potently and selectively inhibit KRAS G12D, G12C, and G12V mutations and WT KRAS, while sparing HRAS, NRAS, and other off-targets. We hypothesize that this potency and selectivity profile, along with high oral bioavailability, will provide efficacy and tolerability for patients with KRAS-mutant-driven cancers. An IND submission is planned in 2024.

Citation Format: Lourdes Prieto Vallejo, Chandrasekar Iyer, Noelle Goggin, Binghui Li, Peiyi Yang, Huimin Bian, Jessica Podoll, Stefan Grotegut, Manuj Tandon, Bryan D Anderson, Andrew Capen, Min Xiao, Tao Wang, Trent R Stewart, Sean Aronow, Desta Bume, Isabel Rojo Garcia, Chong Si, Andrew Cooke, Robert Bondi, Lakshmi Kelamangalath, Ross Wallace, Gabrielle Kolakowski, Lauire LeBrun, James R Henry, Tim Kercher. Preclinical characterization of orally bioavailable, highly potent pan-KRAS inhibitors with selectivity over HRAS and NRAS [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 B116.