Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 60, Issue 29, Pages 15905-15911Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202101328
Keywords
cholangiocarcinoma; degrader; FGFR1; FGFR2; protein degradation
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Funding
- NIH [5 R01 CA218278-02]
- Pediatric Low-Grade Astrocytoma Fund at the Pediatric Brain Tumor Foundation
- V Foundation for Cancer Research
- CCF award - Research Grant from the Cholangiocarcinoma Foundation
- SPORE NIH [P50 CA127003]
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DGY-09-192 is a potential prototype FGFR degrader with high selectivity, preferentially inducing degradation of FGFR1 and 2 while sparing FGFR3 and 4. In clinically relevant models, DGY-09-192 demonstrated the ability to degrade FGFR2 fusion proteins.
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.
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