GFH276's Preclinical Research Results Posted at 2025 AACR

GFH276: A molecular glue Pan RAS (ON) inhibitor with broad spectrum anti-tumor activities

Abstract No.: 389

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.

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.

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.

About GenFleet Therapeutics

With a focus on cutting-edge therapies, GenFleet Therapeutics is dedicated to serving significant unmet medical needs globally in oncology and immunology. Leveraging its deep understanding of disease biology and translational medicine, GenFleet has established a proprietary and fully integrated R&D system that yields a robust pipeline of multiple cutting-edge products with novel mechanisms and global IP.

Since its inception in 2017, GenFleet has built up industry-leading capabilities and expertise in developing novel drug candidates spanning small molecules and biologics. Its pipeline comprises numerous programs that have advanced to later-stage or pivotal clinical trials across China, the United States and Europe. Dupert® (fulzerasib) is the first approved KRAS G12C inhibitor in China and the third globally; it also received NDA priority review designation and two breakthrough therapy designations. Additionally, the first-line combination therapy of fulzerasib and cetuximab has progressed into phase II study in Europe, marking the world's first integration of KRAS and EGFR inhibitors for first-line non-small cell lung cancer treatment. 

With proven success in developing RAS-pathway targeted therapies, GenFleet is also vigorously expanding its portfolio that includes other innovative therapies and novel modalities. Furthermore, it's strengthening its commercial collaborative network through strategic out-licensing agreements or clinical cooperations with prestigious listed companies across the world.

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