Fibroblast growth factor receptor 1 Puns

Current approved FGFR inhibitors lack selectivity within the FGFR family, which may contribute to their poor tolerability. Here, we describe DGY-09-192, a selective FGFR1&2 degrader that destabilized wildtype FGFR1&2 and FGFR2 fusion proteins, had potent anti-proliferative activity in FGFR2-dependent cells, and possessed pharmacokinetics properties suitable for in vivo degradation. Thus, FGFR degradation may be a promising therapeutic approach.

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 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.

https://ift.tt/2ReugeG

http://www.ncbi.nlm.nih.gov/pubmed/24134151

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.

https://ift.tt/2ReugeG