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.
Guangyan Du  1  2 ,  Jie Jiang  1  2 ,  Qibiao Wu  3  4 ,  Nathaniel J Henning  1  2 ,  Katherine A Donovan  1  2 ,  Hong Yue  1  2 ,  Jianwei Che  1  2 ,  Wenchao Lu  1  2 ,  Eric S Fischer  1  2 ,  Nabeel Bardeesy  3  4 ,  Tinghu Zhang  5 ,  Nathanael S Gray  5
Affiliations
  • 1. Department of Cancer Biology, Dana Farber Cancer Institute, 360 Longwood Ave, Boston, MA, 02215, USA.
  • 2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 3. Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 4. Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • 5. Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, USA.
PMID: 33915015 DOI: 10.1002/anie.202101328
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.
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