Biological Activity
H3B-6527 is a highly selective covalent FGFR4 inhibitor with IC50 < 1.2 nM, with >250-fold selectivity for FGFR4 over FGFR1-3 (IC50s of 320, 1290 and 1290 for FGFR1-3, respectively) 1060 nM).
in vitro
H3B-6527 has a strong inhibitory effect on FGFR4 with IC50 less than 1.2 nM. TAOK2, JNK2 and CSF1R were less sensitive to H3B-6527 treatment with IC50s of 690, >10000 and >10000 nmol/L, respectively. Treatment of Hep3B cells with H3B-6527 resulted in a concentration-dependent activation of caspase-3/7. It inhibits FGFR4 signaling, inhibits proliferation, and causes apoptosis in HCC cells.
in vivo
In a mouse model of Hep3B hepatocarcinoma xenografts, H3B-6527 had dose-proportional plasma exposure (greater than tumor exposure; doses tested were 30, 100, and 300 mg/kg). The pharmacodynamic response of H3B-6527 was detected, and it was found that CYP7A1 mRNA and pERK1/2 protein levels showed a concentration-dependent response, and higher concentrations would lead to a more durable response. In both subcutaneous Hep3B xenograft models and orthotopic xenograft models, oral administration of it (twice a day) significantly inhibited the growth of xenografts. Palbociclib enhanced the potency of it and promoted tumor regression in the JHH-7 model, whereas it single-agent administration only caused tumor growth arrest.
