H3B-6527

H3B-6527 is an inhibitor of FGF receptor 4 (FGFR4; IC₅₀ = <1.2 nM).¹ It is selective for FGFR4 over a panel of 395 kinases, including FGFR1, FGFR2, and FGFR3 (IC₅₀s = 320, 1,290, and 1,060 nM, respectively), as well as TAOK2, JNK2, and CSF1R (IC₅₀s = 690, >10,000, and >10,000 nM, respectively). H3B-6527 increases the expression of the cytochrome P450 (CYP) isoform CYP7A1 and decreases phosphorylation of ERK1/2 in Hep3B hepatocellular carcinoma (HCC) cells in a concentration-dependent manner, indicating inhibition of the FGF19-FGFR4 signaling pathway. It also decreases cell growth (GI₅₀ = 25 nM) and increases caspase-3/7 activity in Hep3B HCC cells. H3B-6527 selectively inhibits cell growth in HCC cell lines that express high levels of FGF19 and have high FGF19 protein levels. It reduces tumor growth in a Hep3B HCC mouse xenograft model, when administered at doses of 100 and 300 mg/kg, and in patient-derived xenograft models with high FGF19 expression. H3B-6527, in combination with PD 0332991 (palbociclib; Item No. 16273), induces tumor stasis in a JHH-7 mouse xenograft model.

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1. Joshi, J.J., Coffey, H., Corcoran, E., et al. H3B-6527 is a potent and selective inhibitor of FGFR4 in FGF19-driven hepatocellular carcinoma. Cancer Res. 77(24), 6999-7013 (2017).