GenFleet Therapeutics, a commercial-stage biopharmaceutical company focusing on cutting-edge therapies in oncology and immunology, today announced the latest preclinical findings of GFH276, an IND-enabling oral Pan RAS (ON) inhibitor, at the poster presentation of the 2025 American Association for Cancer Research (AACR) Annual Meeting.
GFH276 is developed with the novel mechanism by recruiting intracellular cyclophilin A (CypA) protein to target RAS proteins across most wild-type/mutant subtypes, and exerted potent anti-tumor activities in cellular & tumor models harboring RAS mutations or RTK alterations. In preclinical research, GFH276 also demonstrated profound inhibition of MAPK signaling pathway. Across multiple KRAS-mutant tumor models, GFH276 displayed superior pharmacokinetic properties and achieved equivalent or enhanced tumor regression at substantially lower effective dosages compared to overseas Pan RAS inhibitor. Notably, GFH276 exhibited no off-target activity in kinase selectivity or safety evaluation, and cellular assays suggested the potential of GFH276 to overcome multiple drug resistances induced by diverse mechanisms.
Abstract Titile | GFH276: A molecular glue Pan RAS (ON) inhibitor with broad spectrum anti-tumor activitiesAbstract（Abstract No.: 389）
Inhibition of most GTP-bound wild-type/mutant RAS subtypes and the downstream MAPK signaling pathway
GFH276 is a molecular glue Pan RAS inhibitor that targets most GTP-bound wild-type and mutant RAS subtypes, by reshaping and repurposing intracellular CypA into the CypA-GFH276-RAS tripartite complex. GFH276 was also observed with potent growth inhibition across an array of KRAS-mutant or RTK-altered cell lines.Notably, GFH276 demonstrated rapid and deep inhibition of phospho-ERK1/2 levels in the MAPK pathway across KRAS-mutant cellular & tumor models. By activating downstream signaling pathways like the MAPK cascade, RAS plays a key role in regulating essential cellular processes including proliferation, migration and survival.
Equivalent/enhanced tumor regression at much lower effective dosages and superior PK properties compared to overseas Pan RAS inhibitor
Over 2-3 weeks’ continuous dosing, GFH276 outperformed RMC-6236 across non-small cell lung cancer, pancreatic cancer, and colorectal cancer models harboring KRAS mutations (G12C, G12D, G12V and G13D etc.): GFH276 demonstrated dose-dependent anti-tumor activity at oral dosages of 0.3-3 mg/kg QD; GFH276 also exhibited equivalent or greater tumor regression at oral dosages of 1 or 3 mg/kg QD, compared to the oral administration of RMC-6236 at 10 mg/kg QD. The advantage of GFH276 in much lower effective dosages is associated with its better pharmacokinetic properties: GFH276’s clearance rate in animal models was significantly lower than that of RMC-6236, while the oral bioavailability of GFH276 markedly higher. Moreover, GFH276 showed no off-targets activity in kinase selectivity and safety assessment, indicating its safety profile and target specificity.
Therapeutic potential to overcome multiple resistances
RTK proteins can be reactivated by EGF stimulation and induced adaptive resistance. Compared to SIIP-based KRAS G12C inhibitors, GFH276 is not susceptible to upstream RTK reactivation by EGF stimulation; the suppression of p-ERK1/2 phosphorylation was barely affected in cellular assays, showcasing the mechanistic advantage of GFH276 in addressing the adaptive resistance. Additionally, GFH276 remained effective across cell lines carrying various acquired resistances to first-generation marketed KRAS inhibitors, highlighting the therapeutic potential of GFH276 as next-generation Pan RAS inhibitor in overcoming multiple resistances.
About RAS and GFH276
RAS proteins, in active GTP-bound or inactive GDP-bound form, are binary molecular switches controlling cellular responses in signaling pathways including RAF-MEK-ERK、PI3K/AKT/mTOR. Three RAS genes encode for protein isoforms, namely Kirsten Ras (KRAS), Harvey Ras (HRAS) and Neuroblastoma Ras (NRAS), and KRAS is the most frequently mutated oncogene in humans.GFH276 is an oral novel small-molecule Pan RAS (ON) inhibitor hijacking Cyp A to target active, GTP bound RAS proteins of most wild/mutant subtypes, including most commonly found KRAS mutant (G12C, G12D, G12V, etc.) proteins. Preclinical research of GFH276 demonstrates dose-dependent anti-tumor activity and drives tumor regression in multiple KRAS mutant tumor models. GFH276 is also superior to the mainstream SIIP (switch II pocket)-based KRAS inhibitors in overcoming adaptive and acquired resistance.
