Design, synthesis and antitumor activity of a novel FGFR2-selective degrader to overcome resistance of the FGFR2V564F gatekeeper mutation based on a pan-FGFR inhibitor

Aberrant activation of Fibroblast Growth Factor receptors (FGFRs) contributes to the development and progression of multiple types of Cancer. Although many FGFR inhibitors have been approved by the FDA, their long-term therapeutic efficacy is hampered by acquired resistance to gatekeeper mutations and low subtype selectivity. FGFR2 has been found to be frequently amplified or mutated in many tumors. In this study, we designed several PROTACs with different E3 ligands based on LY2874455. By screening the length of the linker and the binding site in various degraders, we obtained a novel and highly efficient FGFR2-selective degrader 28e (DC₅₀ = 0.645 nM, DC_max = 86 %). Compound 28e selectively degraded FGFR2 and essentially avoided degradation of FGFR1,3,4 isoforms (DC₅₀ > 300 nM). Compound 28e significantly inhibited the proliferation of FGFR2-overexpressing cell lines, including KATOIII, SNU16, and AN3CA (IC₅₀ = 0.794 nM/0.207 nM/4.626 nM), comparable to parental inhibitors. At the same time, the preferred compound showed superiority over the parental inhibitor in kinase inhibitory activity against the gatekeeper mutant isoform FGFR2^V564F (IC₅₀ = 0.121 nM). In summary, we identified 28e as a novel selective degrader of FGFR2 with high potency and high potential to overcome resistance to gatekeeper mutation. The discovery of 28e provides new evidence for the strategy of pan-inhibitor-based development of selective degrading agents.

Antitumor agents; FGFR2; Gatekeeper mutation; PROTAC.