Discovery of Fulzerasib (GFH925) for the Treatment of KRAS G12C-Mutated Solid Tumors
Tao Jiang, Chonglan Lin, Siyuan Le, Leitao Zhang, Liang Tao, Lijian Cai, Xiaoling Lan, Mei Ge, Zhubo Liu, He Wan, Ling Peng, Yan Zha, Jinmin Ren, Feng Yan, Qiang Lü, Jiong Lan, Fusheng Zhou
Abstract
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.