| In Vitro | In vitro activity: H3B-6527 potently inhibits the FGFR4 kinase with an IC50 value of<1.2 290='' l='' and='' at='' least='' 250-fold='' selectivity='' over='' fgfr1-3='' ic50='' values='' of='' 060='' .='' csf1r='' are='' also='' less='' sensitive='' to='' h3b-6527='' treatment='' with=''>10,000, and>10,000 nmol/L, respectively. H3B-6527 inhibits FGFR4 signaling, proliferation, and leads to apoptosis in a HCC cell line (Hepatocellular carcinoma). Treatment on Hep3B cells leads to robust activation of caspase-3/7, an apoptotic marker, in a concentration-dependent manner, indicating FGFR4 inhibition by H3B-6527 leads to cell death in HCC cell lines. H3B-6527 has the selectivity and the selective dependence on FGFR4 across cancer types.
Kinase Assay:
Cell Assay: Hep3B cells were treated with H3B-6527 at 100 and 300 nmol/L for 0.5, 1, 2, 4, 8, and 24 hours and pERK1/2 levels are measured. |
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| In Vivo | In Hep3B human HCC xenograft mouse model, H3B-6527 displays dose-proportional plasma exposures and greater than dose-proportional tumor exposures within the dose range evaluated (30, 100, and 300 mg/kg). The pharmacodynamic response of H3B-6527 as measured by CYP7A1 mRNA and pERK1/2 protein levels is dose dependent, with higher doses leading to sustained responses. Oral treatment of H3B-6527, twice daily, inhibits xenograft growth in a dose-dependent manner in nude mice, with the 300 or 100 mg/kg twice daily, significantly inhibiting tumor growth in both Hep3B subcutaneous and orthotopic xenograft model and causing tumor regressions in the subcutaneous xenograft model. Palbociclib can enhance H3B-6527 efficacy and promote tumor regression in JHH-7 model where H3B-6527 as a single agent can only lead to tumor stasis. |
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