Design, synthesis, and biological evaluation of novel FGFR1 PROTACs

Dysregulation of the Fibroblast Growth Factor receptor 1 (FGFR1) signaling has prompted efforts to develop therapeutic agents, which is a carcinogenic driver of many cancers, including breast, prostate, bladder, and chronic myeloid leukemia. Despite significant progress in the development of potent and selective FGFR inhibitors, the long-term efficacy of these drugs in Cancer therapy has been hampered by the rapid onset of acquired resistance. Therefore, more drug discovery strategies are needed to promote the development of FGFR-targeted drugs. Here, we discovered compound S2h, a compound that selectively and effectively degrades FGFR1 at nanomolar concentrations in KG1a cells (IC₅₀ = 26.81 nM; DC₅₀ = 39.78 nM), which incorporates an essential, nine atom-long linkers. The importance of linker length, composition, and tethering site proteolysis-targeting chimeras (PROTACs) design is emphasized, and slight modifications can significantly affect degradation potency. Meanwhile, it was verified that the degradation of FGFR1 protein at compound S2h was concentration- and time-dependent and that the protein degradation occurred through the ubiquitin-proteasome system (UPS). In summary, the newly designed heterobifunctional FGFR1 degrader, compound S2h, provides new ideas and references for the research of FGFR small-molecule degraders.

Antitumor activity; E3 ubiquitin ligases; FGFR1; FGFR1 degraders; PROTAC molecules.