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Published on: November 9, 2020
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.
Abstract:
The aberrant activation of FGFR acts as a potent driver of multiple types of human cancers. Despite the development of several conventional small-molecular FGFR inhibitors, their clinical efficacy is largely compromised because of low selectivity and side effects. In this study, we report the selective FGFR1/2-targeting proteolysis-targeting chimera BR-cpd7 that displays significant isoform specificity to FGFR1/2 with half maximal degradation concentration values around 10 nmol/L while sparing FGFR3. The following mechanistic investigation reveals the reduced FGFR signaling, through which BR-cpd7 induces cell-cycle arrest and consequently blocks the proliferation of multiple FGFR1/2-dependent tumor cells. Importantly, BR-cpd7 has almost no antiproliferative activity against cancer cells without FGFR aberrations, furtherly supporting its selectivity. In vivo, BR-cpd7 exhibits robust antitumor effects in FGFR1-dependent lung cancer at well-tolerated dose schedules, accompanied by complete FGFR1 depletion. Overall, we identify BR-cpd7 as a promising candidate for developing a selective FGFR1/2-targeted agent, thereby offering a new therapeutic strategy for human cancers in which FGFR1/2 plays a critical role.
Insights
A novel proteolysis targeting chimeric (PROTAC) molecule, BR-cpd7, selectively targets fibroblast growth factor receptor 1 and 2 (FGFR1/2) to inhibit cancer cell proliferation. This targeted approach shows promise for treating cancers driven by FGFR1/2 aberrations.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Aberrant fibroblast growth factor receptor (FGFR) activation drives various human cancers.
- Existing small-molecular FGFR inhibitors face challenges with selectivity and side effects.
Purpose of the Study:
- To develop and evaluate a selective FGFR1/2-targeting proteolysis targeting chimeric (PROTAC) molecule, BR-cpd7.
- To assess the anti-cancer efficacy and selectivity of BR-cpd7 in preclinical models.
Main Methods:
- Design and synthesis of BR-cpd7, a PROTAC targeting FGFR1/2.
- In vitro assessment of isoform specificity and anti-proliferative activity against cancer cell lines.
- In vivo evaluation of BR-cpd7 efficacy and tolerability in FGFR1-dependent lung cancer models.
Main Results:
- BR-cpd7 demonstrated high isoform specificity for FGFR1/2 (DC50 ~10 nM), sparing FGFR3.
- BR-cpd7 induced cell cycle arrest and inhibited proliferation in FGFR1/2-dependent cancer cells.
- In vivo studies showed robust anti-tumor effects and FGFR1 depletion in lung cancer models at well-tolerated doses.
Conclusions:
- BR-cpd7 is a promising selective FGFR1/2-targeted agent.
- BR-cpd7 offers a potential new therapeutic strategy for cancers with FGFR1/2 aberrations.
- The PROTAC approach provides enhanced selectivity compared to conventional inhibitors.
