Lirafugratinib (RLY-4008, RYL4008) is a potent, highly selective and irreversible FGFR2 inhibitor with biochemical IC50 of <100 nM, shows high cellular potency (IC50=6 nM, pFGFR; pERK, IC50=3 nM).
RLY-4008 demonstrates > 200‑fold selectivity over FGFR1, and > 80‑ and > 5000‑fold selectivity over FGFR3 and FGFR4, respectively, in biochemical assays.
RLY‑4008 also demonstrates high kinome selectivity for FGFR2 against a panel of > 400 human kinases.
RLY‑4008 has strong activity against primary and acquired FGFR2 resistance mutations in cellular assays, and potent antiproliferative effects on FGFR2‑altered human tumor cell lines.
RLY‑4008 demonstrates dose‑dependent reduction of phosphorylation of FGFR2 signaling pathway nodes and induction of apoptosis.
RLY‑4008 inhibits cellular proliferation with IC50 < 14 nM in FGFR2 fusion‑positive, FGFR2‑amplified, and FGFR2‑mutant cancer cell lines. RLY‑4008 does not have strong inhibitory activity in FGFR1, FGFR3 or FGFR4‑dependent cell lines, demonstrating the exquisite selectivity of RLY‑4008 on FGFR2 in cellular assays.
RLY‑4008, administered orally, twice daily from 1 to 30 mg/kg, exhibits dose‑dependent antitumor activity and induces tumor regression in subcutaneous xenograft tumor models harboring FGFR2
alterations.
RLY‑4008 induces regression in xenograft models expressing FGFR2V565F and FGFR2N549K, two common FGFR2 kinase domain mutations that drive clinical progression on current pan‑FGFR inhibitors.
