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

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.