Abstract 4367: ERAS-4001 is a pan-KRAS inhibitor with robust anti-tumor activity in KRAS altered solid tumors

Abstract KRAS is one of the most frequently mutated proteins in cancer (approximately 16% of all cancers), including non-small cell lung (∼30%), pancreatic (∼90%), colorectal (∼40%), and other cancers. Targeting both wild type (WT) KRAS and oncogenic KRAS mutant proteins within the tumor cell is a potentially more promising therapeutic strategy than targeting the mutant KRAS protein alone since WT KRAS activity can act as a resistance mechanism to mutant selective KRAS inhibition. Pan-KRAS inhibitors enable simultaneous mutant/WT KRAS inhibition and have the potential to show improved tolerability relative to pan-RAS inhibitors by sparing NRAS and HRAS. ERAS-4001 is a novel pan-KRAS inhibitor that binds to WT KRAS and KRAS G12X mutants and prevents KRAS from signaling downstream via effector proteins, such as the RAF protein family, with single digit nanomolar potency. ERAS-4001 was selective for KRAS G12X mutants and WT KRAS over WT HRAS and WT NRAS in surface plasmon resonance (SPR) studies, possibly providing an expanded therapeutic index. In the biochemical KRAS G12D-RAF1 RBD (RAS-binding domain protein) assay, ERAS-4001 inhibited complex formation when KRAS G12D was either in the active state (i.e., GMPPNP-bound) or inactive state (i.e., GDP-bound) with single digit nanomolar IC50s. ERAS-4001 showed potent cellular activity in a panel of KRAS WT amplified and KRAS G12X mutant NSCLC, PDAC, and CRC cell lines in both ERK1/2 phosphorylation (pERK) inhibition and 3-dimensional Cell-Titer Glo (3D-CTG) assays with IC50s in the range of 0.7-56 nM. In vivo, oral administration of ERAS-4001 at 100 mg/kg BID resulted in significant tumor growth inhibition in KRAS G12D and G12V mutant subcutaneous xenograft models from 77% TGI to 83% tumor regression. ERAS-4001 achieved a dose dependent increase in plasma concentrations and significant concomitant reduction in pERK. We hypothesize that the potency and selectivity profile of the pan-KRAS inhibitor ERAS-4001 will provide efficacy and tolerability for patients with tumors driven by oncogenic KRAS alterations. An IND submission is intended for the first quarter of 2025. Citation Format: Jae Hyun Bae, Bingzhen Lin, Erin D. Lew, Alexei Brooun, Joanne Oh, Taylor Sullivan, Corine Holub, Alex Stromitis, Brian Qua, Robert F. Shoemaker. ERAS-4001 is a pan-KRAS inhibitor with robust anti-tumor activity in KRAS altered solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4367.