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

Although
FGFR inhibitors hold promise in treating various cancers,
resistance to the FGFR inhibitors caused by acquired secondary mutations
has emerged. To discover novel FGFR inhibitors capable of inhibiting
FGFR mutations, including gatekeeper mutations, we designed and synthesized
several new pyridinyltriazine derivatives. A structure–activity
relationship (SAR) study led to the identification of 17a as a highly potent panFGFR inhibitor against wild-type and mutant
FGFRs. Notably, 17a is superior to infigratinib in terms
of kinase-inhibitory and cellular activities, especially against V555M-FGFR3.
Molecular dynamics simulations provide a clear understanding of why
pyridinyltraizine derivative 17a possesses activity against
V555M-FGFR3. Moreover, 17a significantly suppresses proliferation
of cancer cells harboring FGFR mutations via FGFR signaling blockade,
cell cycle arrest, and apoptosis. Furthermore, 17a and 17b exhibited remarkable efficacies in TEL-V555M-FGFR3 Ba/F3
xenograft mouse model and 17a is more efficacious than
infigratinib. This study provides new insight into the design of novel
FGFR inhibitors that are active against FGFR mutants.