Abstract 390: ERAS-0015 is a pan-RAS molecular glue with best-in-class potential in RAS mutant solid tumors

Abstract As a key node of the canonical RTK-RAS-MAPK signaling cascade, the RAS family of GTPases plays an essential role in numerous physiological processes including cellular proliferation, migration, survival, and immune cell activation. However, under pathological conditions, oncogenic RAS mutations, particularly in hotspot codons 12, 13, and 61, affect RAS intrinsic hydrolysis and/or GEF-mediated exchange resulting in a shift from GDP-bound to GTP-bound RAS. This shift to the GTP-bound RAS state leads to recruitment of effector proteins through the RAS-binding domains (RBDs) and ultimately leads to prolonged intracellular activation and modulation of the tumor microenvironment (TME). ERAS-0015 is a pan-RAS molecular glue with best-in-class potential designed to target RAS in the GTP-bound state and shut down cellular signaling mediated by both mutant and wild-type RAS. ERAS-0015 exhibited 3-7-fold more potent inhibition of cellular proliferation relative to RMC-6236, a RAS molecular glue comparator, across multiple RAS mutant cell lines harboring G12X/G13X/Q61X mutations. ERAS-0015’s roughly 8-20-fold higher binding affinity to cyclophilin A (CYPA) is thought to contribute to its higher in vitro cellular potency as well as favorable ADME and PK properties resulting in a longer residence time and greater exposure in tumor tissues as compared to RMC-6236. These favorable properties enabled ERAS-0015 to achieve comparable tumor growth inhibition (TGI) relative to RMC-6236 at 1/8th-1/10th the dose across multiple KRAS mutant CDX models irrespective of histology or specific mutation. ERAS-0015 demonstrated promising preclinical activity across multiple RAS mutant models supporting IND filing in 1H 2025. Citation Format: Erin D. Lew, Alexei Brooun, Justine Lam, Joanne Oh, Taylor Sullivan, Corine Holub, Jae Hyun Bae, Bingzhen Lin, Brian Qua, Alex Stromitis, Sarah M. Griffith, Andrea Shen, Dawei Xuan, Robert F. Shoemaker. ERAS-0015 is a pan-RAS molecular glue with best-in-class potential in RAS mutant 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 390.