H3B-6527

H3B-6527 shows robust inhibition of the target kinase FGFR4 with an IC50 value of <1.2 nmol/L and at least 250-fold selectivity over FGFR1-3 (IC50 values of 320, 1,290 and 1,060 nmol/L respectively). TAOK2, JNK2, and CSF1R are also less sensitive to H3B-6527 treatment with IC50 values of 690, >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^[1].

Hep3B cells are 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.

In the Hep3B human HCC xenograft mouse model, H3B-6527 shows dose-proportional plasma exposures and greater than dose-proportional tumor exposures within the dose range evaluated (30, 100, and 300 mg/kg). The H3B-6527 pharmacodynamic response 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.