Lirafugratinib hydrochloride

• CAT Number: I043417
• CAS Number: 2688040-45-9
• Molecular Formula: C28H25ClFN7O2
• Molecular Weight: 546.00
• Purity: ≥95%
• Synonyms: N-[4-[4-amino-5-[3-fluoro-4-(4-methylpyrimidin-2-yl)oxyphenyl]-7-methylpyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-2-methylprop-2-enamide;hydrochloride
• InChI: InChI=1S/C28H24FN7O2.ClH/c1-15(2)27(37)35-19-8-5-17(6-9-19)24-22(23-25(30)32-14-33-26(23)36(24)4)18-7-10-21(20(29)13-18)38-28-31-12-11-16(3)34-28;/h5-14H,1H2,2-4H3,(H,35,37)(H2,30,32,33);1H
• InChIKey: HLGJPRBWELSHLI-UHFFFAOYSA-N
• SMILES: CC1=NC(=NC=C1)OC2=C(C=C(C=C2)C3=C(N(C4=NC=NC(=C34)N)C)C5=CC=C(C=C5)NC(=O)C(=C)C)F.Cl

Lirafugratinib (RLY-4008) hydrochloride is an orally active, irreversible and highly selective FGFR2 inhibitor with an IC50 of 3 nM. Lirafugratinib hydrochloride covalently binds to Cys491. Lirafugratinib hydrochloride targets FGFR2 primary alterations and resistance mutations and induces tumor regression while sparing other FGFRs[1].
Lirafugratinib (RLY-4008) hydrochloride 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) hydrochloride induces dose-dependent cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP)-early markers of apoptosis[1].
Lirafugratinib (2h) hydrochloride 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].
Lirafugratinib (RLY-4008; 1-30 mg/kg; orally, twice daily; 15-30 days) hydrochloride demonstrates antitumor activity in FGFR2-altered cancer xenograft models[1].

Reference

[1]. Vivek Subbiah, et al. RLY-4008, the First Highly Selective FGFR2 Inhibitor with Activity across FGFR2 Alterations and Resistance Mutations. Cancer Discov. 2023 Sep 6;13(9):2012-2031.
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