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

  • J Med Chem. 2025 Jul 10;68(13):13858-13871. doi: 10.1021/acs.jmedchem.5c00731.
Lulu Zheng  1  2 ,  Jiaqi Cao  1 ,  Lin Ma  1 ,  Shiyan Chen  1 ,  Xiansheng Cao  1 ,  Ruixiang Luo  1 ,  Yuhan Wang  1 ,  Di Ke  3 ,  Ping Huang  1  2 ,  Guang Liang  1  2 ,  Lingfeng Chen  1
Affiliations
  • 1. School of Pharmacy, Hangzhou Medical College, Hangzhou 310014, China.
  • 2. Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, China.
  • 3. Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei 230601, China.
PMID: 40575843 DOI: 10.1021/acs.jmedchem.5c00731
Abstract

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.

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