Discovery of a Potent Degrader for Fibroblast Growth Factor Receptor 1/2

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Aberrant fibroblast growth factor receptor (FGFR) signaling drives numerous cancers.
• Approved ATP-competitive FGFR inhibitors show efficacy but suffer from dose-limiting toxicities and poor tolerability due to lack of selectivity.
• Targeted protein degradation offers a promising alternative therapeutic strategy.

Purpose of the Study:

• To discover and characterize a novel FGFR degrader with improved selectivity and reduced toxicity.
• To evaluate the efficacy of the novel degrader in preclinical cancer models.

Main Methods:

• Design and synthesis of DGY-09-192, a bivalent molecule coupling BGJ398 (pan-FGFR inhibitor) to a CRL2VHL E3 ligase ligand.
• Assessment of FGFR degradation and antiproliferative activity in cancer cell lines.
• In vivo evaluation of DGY-09-192 in a xenograft model.

Main Results:

• DGY-09-192 preferentially induced degradation of FGFR1 and FGFR2, while sparing FGFR3 and FGFR4.
• The compound demonstrated potent degradation activity (two-digit nanomolar DC50) against wildtype FGFR2 and FGFR2 fusions.
• Degradation-dependent antiproliferative effects were observed in gastric cancer and cholangiocarcinoma cells.
• In vivo studies showed DGY-09-192 induced degradation of a clinically relevant FGFR2 fusion protein.

Conclusions:

• DGY-09-192 represents a promising prototype FGFR degrader with selective degradation of FGFR1/2.
• This approach holds potential for developing more tolerable and effective cancer therapies targeting FGFR-driven malignancies.
• Targeted protein degradation via DGY-09-192 offers a novel strategy against cancers with FGFR alterations.