Identification of Pyridinyltriazine Derivatives as Potent panFGFR Inhibitors against Gatekeeper Mutants for Overcoming Drug Resistance

Although FGFR inhibitors hold promise in treatingvarious cancers, resistance to the FGFR inhibitors caused byacquired secondary mutations has emerged. To discover novelFGFR inhibitors capable of inhibiting FGFR mutations, includinggatekeeper mutations, we designed and synthesized several newpyridinyltriazine derivatives. A structure-activity relationship(SAR) study led to the identification of17aas a highly potentpanFGFR inhibitor against wild-type and mutant FGFRs. Notably,17ais superior to infigratinib in terms of kinase-inhibitory andcellular activities, especially against V555M-FGFR3. Moleculardynamics simulations provide a clear understanding of whypyridinyltraizine derivative17apossesses activity against V555M-FGFR3. Moreover,17asignificantly suppresses proliferation of cancer cells harboring FGFR mutations via FGFR signaling blockade,cell cycle arrest, and apoptosis. Furthermore,17aand17bexhibited remarkable efficacies in TEL-V555M-FGFR3 Ba/F3 xenograftmouse model and17ais more efficacious than infigratinib. This study provides new insight into the design of novel FGFR inhibitorsthat are active against FGFR mutants.

Automated summary

In this study, we designed and synthesized several new pyridinyltriazine derivatives and identified a highly potent panFGFR inhibitor, 17a, which showed superior inhibitory and cellular activities against both wild-type and mutant FGFRs. 17a exhibited significant suppression of cancer cell proliferation by blocking FGFR signaling, inducing cell cycle arrest, and promoting apoptosis. This study provides new insights into the design of novel FGFR inhibitors targeting FGFR mutants.