Abstract 6736: Discovery and characterization of BH-501284: A non-covalent, pan-KRAS inhibitor for treatment of diverse <i>KRAS</i> -mutant tumors.

Abstract KRAS mutations are among the most prevalent oncogenic drivers, representing 25% of human cancers. While recently approved covalent KRAS G12C inhibitors have demonstrated meaningful clinical benefit, no targeted therapies are currently approved for other KRAS variants. Consequently, a large portion of the KRAS-driven patient population, including those with pancreatic carcinoma (PDAC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC), remain underserved. Furthermore, available G12C inhibitors have modest potency and limited durability of effect in clinic. Research attributed these modest outcomes to adaptive resistance mechanisms associated with secondary KRAS mutations or activation of bypass pathways. This resistance, along with unmet medical needs, has driven the development of new KRAS-directed therapies capable of targeting multiple KRAS mutants. Here, we describe BH-501284, a potent, selective, orally available, non-covalent, pan-KRAS inhibitor, targeting the allosteric switch-II pocket of KRAS. BH-501284 inhibited cell viability and suppressed ERK phosphorylation in KRAS-mutant cells (G12D/C/V/S, G13D) and KRAS WT amplified cells with low to sub-nanomolar activity. BH-501284 also demonstrated greater than 300-fold selectivity against both HRAS and NRAS and showed no anti-proliferative activity in non-RAS driven cells. Raf1 effector binding assay data showed BH-501284 to bind KRAS mutants in the inactive (OFF) state, with binding affinity in the picomolar range as measured by SPR. Cellular wash off studies confirmed that BH-501284 tightly engaged KRAS, similar to covalent inhibitors. This unique target engagement allows BH-501284 to more comprehensively reduce active KRAS proteins than other reversible KRAS (ON) inhibitors. Importantly, the anti-proliferation activity of BH-501284 was only minimally affected by growth factors (e.g. EGF) that drive KRAS into the active state and lead to resistance. Durable and potent activity of BH-501284 was also observed in cell-derived xenograft (CDX) tumor models with KRAS G12D, G12V, and G12C mutations, covering NSCLC, CRC, and PDAC. PK profiling revealed good oral bioavailability of BH-501284 in multiple species and dose dependent plasma exposures in mouse xenograft tumor models. Lastly, BH-501284 showed synergistic effects with inhibitors of EGFR, FAK/SRC, and others in combination studies. Altogether, these findings position BH-501284 as a strong candidate for further development. Citation Format: Nancy Ling, Evan Rogers, Eugene Rui, Wei Deng, Ping Jiang, Zhenping Wang, Yue Hu, Joshua Choi, Danan Li, Anindya Sarkar, Levan Darjania, Geoffrey Oxnard, Jean Cui, . Discovery and characterization of BH-501284: A non-covalent, pan-KRAS inhibitor for treatment of diverse KRAS-mutant tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6736.