Lirafugratinib

Lirafugratinib (RLY-4008) is an orally active, irreversible and highly selective FGFR2 inhibitor with an IC₅₀ of 3 nM. Lirafugratinib covalently binds to Cys491. Lirafugratinib targets FGFR2 primary alterations and resistance mutations and induces tumor regression while sparing other FGFRs^[1]. IC50 & Target:FGFR2^[1] In Vitro:Lirafugratinib (RLY-4008) has >250-fold selectivity over FGFR1, and >80- and >5,000-fold selectivity over FGFR3 and FGFR4, respectively. The reversible binding of Lirafugratinib promotes a rigid and extended P-loop in FGFR1 that disfavors covalent bond formation while minimally affecting the conformation of the P-loop in FGFR2, enabling efficient covalent bond formation and leading to FGFR2 selectivity^[1].
Lirafugratinib (24h) induces dose-dependent cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP)-early markers of apoptosis^[1].
Lirafugratinib (2h) demonstrates a dose-dependent reduction of phosphorylation of FGFR2 signaling pathway nodes, including FRS2, AKT, and ERK^[1].
RLY-4008 inhibits cellular proliferation with IC₅₀<14 nM in FGFR2-dependent cell lines including KATO III, SNU-16 and NCI-H716, ICC13-7, and MFE-296, FGFR2N549K and AN3CA, FGFR2K310R; N549K and JHUEM-2, FGFR2C383R^[1].
In Vivo:Lirafugratinib (RLY-4008; 1-30 mg/kg; orally, twice daily; 15-30 days) demonstrates antitumor activity in FGFR2-altered cancer xenograft models^[1].