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LC-MF-4, a Novel FGFR3 Degrader for Therapeutic Intervention in FGFR3-Altered Cancers
Lulu Zheng1,2, Jiaqi Cao1, Lin Ma1
1School of Pharmacy, Hangzhou Medical College, Hangzhou 310014, China.
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.
Insights
Researchers discovered LC-MF-4, the first effective fibroblast growth factor receptor 3 (FGFR3) degrader. This new drug shows promise for treating cancers with FGFR3 alterations by targeting FGFR3 degradation.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Fibroblast growth factor receptor 3 (FGFR3) gene alterations are implicated in cancers like bladder cancer and urothelial carcinoma (UC).
- Current treatments like erdafitinib for UC face limitations due to resistance mutations.
- Existing FGFR degraders primarily target FGFR1 or FGFR2, leaving an unmet need for FGFR3-specific agents.
Purpose of the Study:
- To identify and characterize the first efficient degrader targeting fibroblast growth factor receptor 3 (FGFR3).
- To evaluate the therapeutic potential of this novel FGFR3 degrader in preclinical cancer models.
Main Methods:
- Discovery and characterization of a novel small molecule, LC-MF-4.
- Proteomic analysis to assess target selectivity and degradation.
- In vitro studies in FGFR3-TACC3 fusion-positive cells to investigate molecular mechanisms.
- In vivo efficacy assessment using a Ba/F3-FGFR3-TACC3 xenograft model.
Main Results:
- LC-MF-4 was identified as the first efficient degrader of FGFR3.
- Proteomic analysis confirmed exceptional selectivity of LC-MF-4 for FGFR3 degradation.
- LC-MF-4 suppressed mitochondrial biogenesis and ATP synthesis gene expression in FGFR3-TACC3 fusion-positive cells.
- Significant antitumor activity was observed in the Ba/F3-FGFR3-TACC3 xenograft model.
Conclusions:
- LC-MF-4 represents a novel therapeutic strategy for cancers with FGFR3 alterations.
- The selective degradation of FGFR3 by LC-MF-4 offers a potential approach to overcome resistance mechanisms.
- This study validates LC-MF-4 as a promising candidate for treating FGFR3-driven malignancies.
