FGFR4 inhibitor,potent and irreversible
CAS：1538604-68-0
分子式：C26H22Cl2N4O3
分子量：509.38
纯度：98%
存储：Store at -20°C

Background:

BLU9931 is a potent and irreversible inhibitor of FGFR4. BLU9931 potently inhibited FGFR4 activity (IC50 = 3 nmol/L), but weakly inhibited FGFR1 (IC50 = 591 nmol/L), FGFR2 (IC50 = 493 nmol/L), and FGFR3 (IC50 = 150 nmol/L) activity.
Fibroblast growth factor receptor 4 (FGFR4) is the receptor of fibroblast growth factor 19 (FGF19), which is a tightly controlled hormone that regulates bile acid synthesis and hepatocyte proliferation in the normal liver. FGFR4 acts as a targeted therapy to treat patients with HCC whose tumors have an activated FGFR4 signaling pathway. BLU9931 is highly selective for FGFR4 versus other FGFR family members and all other kinases. BLU9931 binds within the ATP-binding pocket of FGFR4, forming a covalent bond with Cys552. The anilino-quinazoline core of BLU9931 makes a bidentate hydrogen-bonding interaction with the hinge residue (Ala553) of FGFR4, whereas the dichlorodimethoxyphenyl group occupies the hydrophobic pocket, providing FGFR-family selectivity. BLU9931 displayed significant binding to only two of the 398 wild-type kinases, FGFR4 (99.7% inhibition relative to DMSO control; Kd = 6 nmol/L) and CSF1R (90.1% inhibition relative to DMSO control; Kd = 2716 nmol/L) by KINOMEscan method. [2]
BLU9931 shows remarkable antitumor activity in mice bearing an HCC tumor xenograft that overexpresses FGF19 due to amplification as well as a liver tumor xenograft that overexpresses FGF19 mRNA but lacks FGF19 amplification.
参考文献:
[1]. Hagel M, Miduturu C, Sheets M et al.First Selective Small Molecule Inhibitor of FGFR4 for the Treatment of Hepatocellular Carcinomas with an Activated FGFR4 Signaling Pathway. Cancer Discov. 2015 Mar 16. [Epub ahead of print]
[2]. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol. 2011 Oct 30;29(11):1046-51.