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A Selective FGFR1/2 PROTAC Degrader with Antitumor Activity.
Ying Kong1, Xinyue Zhao2, Zhaofu Wang3
1Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
Molecular Cancer Therapeutics
|June 10, 2024
Summary
A novel agent, BR-cpd7, selectively targets and degrades FGFR1/2, inhibiting cancer cell proliferation. This targeted approach shows promise for treating cancers driven by FGFR1/2 aberrations with reduced side effects.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Aberrant Fibroblast Growth Factor Receptor (FGFR) activation drives various human cancers.
- Existing FGFR inhibitors lack selectivity, leading to compromised efficacy and side effects.
Purpose of the Study:
- To develop and characterize a selective FGFR1/2-targeting agent.
- To evaluate the therapeutic potential of BR-cpd7 in FGFR-driven cancers.
Main Methods:
- Development of a proteolysis-targeting chimera (PROTAC), BR-cpd7.
- Assessment of FGFR isoform specificity and degradation efficacy in vitro.
- Mechanistic studies on cell-cycle arrest and proliferation inhibition.
- In vivo efficacy studies in FGFR1-dependent lung cancer models.
Main Results:
- BR-cpd7 demonstrated high selectivity for FGFR1/2 over FGFR3 (around 10 nmol/L degradation concentration).
- BR-cpd7 induced cell-cycle arrest and blocked proliferation in FGFR1/2-dependent cancer cells.
- Significant antitumor effects and FGFR1 depletion were observed in vivo in lung cancer models.
- BR-cpd7 showed minimal activity against cancer cells lacking FGFR aberrations.
Conclusions:
- BR-cpd7 is a highly selective FGFR1/2 degrader with potent anti-cancer activity.
- BR-cpd7 represents a promising therapeutic candidate for FGFR1/2-driven human cancers.
- This agent offers a novel strategy for targeted cancer therapy with improved selectivity.
