Abstract 389: GFH276: A molecular glue panRAS(on) inhibitor with broad spectrum anti-tumor activities

Abstract KRAS is the most frequently mutated oncogene but had long been considered to be undruggable until the approval of the first KRAS G12C inhibitor Sotorasib for NSCLC treatment in 2021. However, the clinical performance of Sotorasib and other SIIP-based KRAS inhibitors is hindered by their susceptibility to adaptive resistance and rapidly emerging, diverse acquired resistance. Therefore, developing a novel RAS inhibitor being able to overcome the above limitations holds the potential of making the most of RAS-targeted therapies. Here we report the characterization of a preclinical candidate molecular glue panRAS(on) inhibitor- GFH276, designed to target multiple RAS mutants of active, GTP-bound state by recruiting intracellular cyclophilin A (CypA) protein. In biochemical assays, GFH276 disrupted the binding of GMPPNP-bound KRAS G12C, G12D or G12V mutants or wild type KRAS, HRAS or NRAS proteins to RAF1 in a CypA-dependent manner. In cellular assays, GFH276 suppressed phosphor-ERK1/2 (p-ERK) level in KRAS G12C, G12D and G12V-mutated cells with IC50s < 1 nM, and demonstrated potent tumor-suppressive effect in a panel of cell lines carrying different KRAS (G12A, G12C, G12V, G12R, G12S, G13D or Q61K), NRAS (G12D) or HRAS (Q61H) mutations, with IC50s of 0.07-73 nM. In addition, GFH276 was also active in tumor cell lines carrying EGFR or FGFR2/3 alterations but showed no activity in cell lines carrying mutations on downstream BRAF component. In KRAS-mutated xenograft models, oral administration of GFH276 elicited rapid and deep inhibition on p-ERK level in tumor tissues, demonstrated dose-dependent anti-tumor activity and induced tumor regression at dose level as low as 1 mg/kg QD. Compared to SIIP-based KRAS G12C inhibitors Sotorasib, Adagrasib and Divarasib, GFH276 was not susceptible to upstream RTK-reactivation by EGF stimulation and remained effective against cell lines carrying second KRAS mutations or RTK alterations or with induced resistance to Sotorasib. GFH276 showed no off-target activity in 72-kinase selectivity and SafetyScreen44 panel tests. GFH276 showed high bioavailability in mice, rats and dogs (39%-113%). Taken together, GFH276 represents a new generation of RAS inhibitors that are superior to the mainstream SIIP-based KRAS inhibitors in overcoming adaptive and acquired resistance. GFH276 demonstrated strong therapeutic activities in tumors with activating RAS and RTK alterations. Encouraged by these promising results, we are advancing GFH276 into the Phase 1 clinical trial by conducting IND-enabling studies and the IND submission is planned in Q2 2025. Citation Format: Feng Yan, Jichen Zhao, Jingyang Zhang, Hongcan Ren, Siyuan Le, Fusheng Zhou, Jiong Lan, Qiang Lu. GFH276: A molecular glue panRAS(on) inhibitor with broad spectrum anti-tumor activities [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 389.