Discovery of a Potent Degrader for Fibroblast Growth Factor Receptor 1/2
Guangyan Du, Jie Jiang, Qibiao Wu, Nathaniel J. Henning, Katherine A. Donovan, Hong Yue, Jianwei Che, Wenchao Lu, Eric S. Fischer, Nabeel Bardeesy, Tinghu Zhang, Nathanael S. Gray
Abstract
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 CRL2 VHL E3 ligase recruiting ligand, which preferentially induces FGFR1&2 degradation while largely sparing FGFR3&4. DGY‐09‐192 exhibited two‐digit nanomolar DC 50 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.