Discovery of a Potent Degrader for Fibroblast Growth Factor Receptor 1/2

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.

Discovery and Characterisation of Highly Cooperative FAK‐Degrading PROTACs

“…Given the sharp turn created by the acetamide of GSK215,a nd the close proximity of the FAK-and VHL-binding portions,i ti sl ikely that longer linkers would produce different ternary complex structures with alternative positioning of the two proteins.L onger linkers can produce flexible ternary complexes which adopt multiple conformations; [30,33] we hypothesise that while 2 can induce strongly cooperative ternary binding, the rigid GSK215 structure is ak ey factor in its more effective degradation of FAK. Ar ecently reported FGFR-VHL PROTACi ncludes as imilar acetylpiperazine linker, [34] suggesting commonalities in their binding mode and the possibility of transferrable SAR between kinase PROTACs.T his work reinforces the importance of thoroughly surveying linker length and rigidity in PROTACd esign, and the effect small modifications can have on cooperativity and DC 50 .…”

PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

“…In 2021, Gray group synthesized several glutarimide-based CRBN-targeting degraders with various linkers based on FGFR inhibitor BGJ398. 82 Through binding affinity tests and protein-degradation experiments, it was found that the PROTACs based on BGJ398 could degrade TEL-FGFR2 in Ba/F3 cells, while the full-length FGFR2 was poorly degraded in Kato III cells. Therefore, they used VHL ligands to replace CRBN and found the degrader 41 ( DGY-09–192 , Fig.…”

Signaling Pathway and Small-Molecule Drug Discovery of FGFR: A Comprehensive Review

“…Interestingly, the PROTAC mediated the internalization of EGFR and sorted to lysosomal degradation, although the RTKs usually prefer to be internalized into a recycling endosome ( Zou et al, 2019 ). Du et al (2021) recently reported a bivalent degrader DGY-09-192, which coupled pan-FGFR inhibitor BGJ-398 to a CRL2 VHL E3 ligase ( Figure 15 ). Surprisingly, DGY-09-192 preferentially induced FGFR1 and FGFR2 degradation while largely sparing FGFR3 and FGFR4.…”