TYRA-200 represents a next-generation covalent inhibitor specifically engineered to target FGFR2, addressing critical limitations in current therapeutic options. The fibroblast growth factor receptor 2 plays pivotal roles in cellular proliferation and differentiation, with its genetic alterations strongly implicated in intrahepatic cholangiocarcinoma (iCCA) pathogenesis - particularly the FGFR2 fusions observed in 10-15% of iCCA cases. While pan-FGFR inhibitors have recently emerged as treatment options for advanced biliary tract cancers, their clinical utility is frequently compromised by polyclonal resistance mutations, predominantly within the FGFR2 kinase domain. TYRA-200 was developed through structure-guided rational design to overcome these resistance mechanisms.
