Wiley, Angewandte Chemie International Edition, 29(60), p. 15905-15911, 2021
Wiley, Angewandte Chemie, 29(133), p. 16041-16047, 2021
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AbstractAberrant 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 DC50s 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.