H3B-6527(cas 1702259-66-2) is a potent and orally active FGFR4 inhibitor with potential antineoplastic activity. Upon administration, H3B-6527 specifically binds to and blocks FGFR4. This prevents the activation of FGFR4, inhibits FGFR4-mediated signaling and leads to an inhibition of cell proliferation in FGFR4-overexpressing tumor cells.
1. Cancer Res. 2017 Dec 15;77(24):6999-7013. doi: 10.1158/0008-5472.CAN-17-1865.
H3B-6527 Is a Potent and Selective Inhibitor of FGFR4 in FGF19-Driven
Joshi JJ(1), Coffey H(1), Corcoran E(1), Tsai J(1), Huang CL(1), Ichikawa K(1),
Prajapati S(1), Hao MH(1), Bailey S(1), Wu J(1), Rimkunas V(1), Karr C(1),
Subramanian V(1), Kumar P(1), MacKenzie C(1), Hurley R(1), Satoh T(1), Yu K(1),
Park E(1), Rioux N(1), Kim A(1), Lai WG(2), Yu L(1), Zhu P(1), Buonamici S(1),
Larsen N(1), Fekkes P(1), Wang J(1), Warmuth M(1), Reynolds DJ(1), Smith PG(3),
(1)H3 Biomedicine, Cambridge, Massachusetts.
(2)Eisai, Andover, Massachusetts.
(3)H3 Biomedicine, Cambridge, Massachusetts. [email protected]
Activation of the fibroblast growth factor receptor FGFR4 by FGF19 drives
hepatocellular carcinoma (HCC), a disease with few, if any, effective treatment
options. While a number of pan-FGFR inhibitors are being clinically evaluated,
their application to FGF19-driven HCC may be limited by dose-limiting toxicities
mediated by FGFR1-3 receptors. To evade the potential limitations of pan-FGFR
inhibitors, we generated H3B-6527, a highly selective covalent FGFR4 inhibitor,
through structure-guided drug design. Studies in a panel of 40 HCC cell lines and
30 HCC PDX models showed that FGF19 expression is a predictive biomarker for
H3B-6527 response. Moreover, coadministration of the CDK4/6 inhibitor palbociclib
in combination with H3B-6527 could effectively trigger tumor regression in a
xenograft model of HCC. Overall, our results offer preclinical proof of concept
for H3B-6527 as a candidate therapeutic agent for HCC cases that exhibit
increased expression of FGF19. Cancer Res; 77(24); 6999-7013. ©2017 AACR.