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

Angew Chem Int Ed Engl. 2021 Jul 12;60(29):15905-15911. doi: 10.1002/anie.202101328. Epub 2021 Jun 14.

Abstract

Aberrant activation of FGFR signaling occurs in many cancers, and ATP-competitive FGFR inhibitors have received regulatory approval. Despite demonstrating clinical efficacy, these inhibitors exhibit dose-limiting toxicity, potentially due to a lack of selectivity amongst the FGFR family and are poorly tolerated. Here, we report the discovery and characterization of DGY-09-192, a bivalent degrader that couples the pan-FGFR inhibitor BGJ398 to a CRL2VHL E3 ligase recruiting ligand, which preferentially induces FGFR1&2 degradation while largely sparing FGFR3&4. DGY-09-192 exhibited two-digit nanomolar DC50 s for both wildtype FGFR2 and several FGFR2-fusions, resulting in degradation-dependent antiproliferative activity in representative gastric cancer and cholangiocarcinoma cells. Importantly, DGY-09-192 induced degradation of a clinically relevant FGFR2 fusion protein in a xenograft model. Taken together, we demonstrate that DGY-09-192 has potential as a prototype FGFR degrader.

Keywords: FGFR1; FGFR2; cholangiocarcinoma; degrader; protein degradation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Drug Discovery*
  • Humans
  • Proteolysis / drug effects*
  • Receptor, Fibroblast Growth Factor, Type 1 / metabolism*
  • Receptor, Fibroblast Growth Factor, Type 2 / metabolism*

Substances

  • Receptor, Fibroblast Growth Factor, Type 1
  • Receptor, Fibroblast Growth Factor, Type 2