LC-MF-4, a Novel FGFR3 Degrader for Therapeutic Intervention in FGFR3-Altered Cancers

作者：Lulu Zheng, Jiaqi Cao, Lin Ma, Shiyan Chen, Xiansheng Cao, Ruixiang Luo, Yuhan Wang, Di Ke, Ping Huang, Guang Liang, Lingfeng Chen · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.5c00731 · 被引用次数：7 · 研究领域：Fibroblast Growth Factor Research、Kruppel-like factors research、Epigenetics and DNA Methylation

Alterations in the fibroblast growth factor receptor 3 (FGFR3) gene have been noted in human diseases, including bladder cancer and urothelial carcinoma (UC). Erdafitinib was approved for the treatment of UC but is limited by the progression of on-target gatekeeper resistance mutations. Several heterobifunctional FGFR degraders have been developed as potential therapeutic agents to block FGFR1 or FGFR2 signaling. However, to date, none of the FGFR3-active degraders have been identified. Herein, we report the discovery of LC-MF-4, the first efficient FGFR3 degrader, for the treatment of cancers harboring FGFR3 alterations. Proteomic analysis revealed that LC-MF-4 exhibits exceptional proteomic selectivity for FGFR3 degradation. In FGFR3-TACC3 fusion-positive cells, LC-MF-4 exerted its effects by suppressing the expression of genes involved in mitochondrial biogenesis and ATP synthesis. This study demonstrated robust antitumor activity of LC-MF-4 in the Ba/F3-FGFR3-TACC3 xenograft model, highlighting its potential for the treatment of FGFR3-altered cancers.