Tao Jiang, Chonglan Lin, Siyuan Le, Leitao Zhang, Tao Liang, Lijian Cai, Xiaoling Lan, Mei Ge, Zhubo Liu, Wan He, Ling Peng, Yanhui Zhao, Jinmin Ren, Feng Yan, Qiang Lu, Jiong Lan, and Fusheng Zhou
J. Med. Chem. 2025, 68, 15, 15386–15402
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.
