Discovery of Fulzerasib (GFH925) for the Treatment of KRAS G12C-Mutated Solid Tumors

RAS mutations are the most prevalent genetic alterations
in human
tumors, accounting for 30% of all cases. Among these mutations, KRAS
G12C emerged as the first druggable target through covalent attachment,
which locks the protein in its inactive state. Employing a structure-based
drug design strategy, we identified fulzerasib (GFH925), which features
a novel lactam-based tetracyclic naphthyridinone scaffold. This molecule
demonstrates high in vitro potency and selectivity,
favorable pharmacokinetic profiles across species, and significant in vivo antitumor efficacy in various cancer-related xenograft
models, including intracranial tumors. Fulzerasib has recently received
accelerated approval in China for adult NSCLC patients with the KRAS
G12C mutation after prior systemic therapy.