Discovery and preclinical characterization of KRAS G12C inhibitor fulzerasib (GFH925) for advanced solid tumors

Human tumors predominantly feature RAS mutations as their most common genetic alteration, present in approximately 30% of all cases. Notably, among the various types of RAS mutations, the KRAS G12C mutation stands out as the first targetable variant. Here, we present our discovery of fulzerasib (GFH925), the third approved KRAS G12C selective inhibitor for second or later-line treatment of advanced NSCLC as a monotherapy. A conformation-driven cyclization strategy enabled the creation of several chemically stable fused tetracyclic cores, with lactam-based scaffold demonstrating optimal pharmacokinetics, including low clearance, high exposure, and excellent oral bioavailability in mice. Subsequent optimization focused on enhancing in vitro potency and reducing CYP3A4-M inhibition through chlorine substitution at the core C11 position, while maintaining favorable solubility. Through structure-based drug design, we successfully developed fulzerasib (GFH925), a novel KRAS G12C inhibitor featuring a tetracyclic naphthyridinone scaffold. Fulzerasib exhibited strong in vitro potency and exquisite selectivity against the oncogenic KRAS G12C mutation. It showed favorable oral bioavailability with an excellent pharmacokinetic profile across species and broad-spectrum anti-tumor efficacy across xenograft models of pancreatic (MIA PaCa-2), colorectal (SW837), and lung (NCI-H358 & LU2529) cancers, including the H1373-luc intracranial CDX model. Notably, in the MIA PaCa-2 and NCI-H358 CDX models, the anti-tumor efficacy of GFH925 was superior to sotorasib at the same dose. In the NCI-H2122 NSCLC model, the concurrent administration of GFH925 and cetuximab significantly suppressed tumor growth and demonstrated preferable synergy in antitumor effects. The comprehensive preclinical evaluation of the rationally designed KRAS G12C inhibitor fulzerasib (GFH925) sets a solid foundation for its rapid clinical advancement in KRAS G12C-driven malignancies.