Synthesis and identification of a selective FGFR2 degrader with potent antiproliferative effects in gastric cancer.

Despite numerous efforts to develop FGFR inhibitors for cancer treatment, the widespread clinical application of currently available FGFR inhibitors has been significantly limited due to the serious side effects caused by poor selectivity and resistance. PROTAC technology, a method for protein degradation, has shown notable advantages over conventional inhibitors. In our study, we coupled Erdafitinib , a pan-FGFR inhibitor, with a CRBN binder to synthesize and identify an effective FGFR2 degrader, N5. Our findings demonstrated that N5 displayed notable specificity for FGFR2 and outstanding enzyme inhibitory capabilities, achieving an IC 50 value of 0.08 nM against FGFR2, and strong antiproliferative activity, maintaining an inhibitory rate above 50% on gastric cancer cells at a concentration of 0.17 nM. Mechanistically, N5 induced gastric cancer cell cycle arrest at the G0/G1 phase and apoptosis by decreasing the levels of FGFR downstream proteins. Moreover, N5 demonstrated favorable pharmacokinetic characteristics with a bioavailability of 74.8% when administered intraperitoneally and effectively suppressed the growth of SNU16 xenograft tumors, exhibiting greater potency compared to the parental inhibitor Erdafitinib. This study lays the groundwork for developing and potentially applying therapeutic agents targeting FGFR2 degradation. [Display omitted] • N5 is a selective and effective FGFR2 degrader. • N5 is a high-affinity PROTAC with an IC 50 of 0.08 nM against FGFR2. • N5 induces G0/G1 cell cycle arrest and apoptosis in gastric cancer cells. • N5 presents favorable pharmacokinetic properties. • N5 is efficacious and well-tolerated in vivo. [ABSTRACT FROM AUTHOR]