Title of article :
Synthesis and biological evaluation of 1-(2,4,5-trisubstituted phenyl)-3-(5-cyanopyrazin-2-yl)ureas as potent Chk1 kinase inhibitors
Author/Authors :
Gaoquan Li، نويسنده , , Lisa A. Hasvold، نويسنده , , Zhi-Fu Tao، نويسنده , , Gary T. Wang، نويسنده , , Stephen L. Gwaltney II، نويسنده , , Jyoti Patel، نويسنده , , Peter Kovar، نويسنده , , Robert B. Credo، نويسنده , , Zehan Chen، نويسنده , , Haiying Zhang، نويسنده , , Chang Park، نويسنده , , Hing L. Sham، نويسنده , , Thomas Sowin، نويسنده , , Saul H. Rosenberg، نويسنده , , Nan-Horng Lin، نويسنده ,
Abstract :
Based on the X-ray crystallography of our lead compound 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-cyanopyrazin-2-yl)urea in the checkpoint kinase 1 (Chk1) enzyme, we modified R4, and to a lesser extent, R2, and R5 of the phenyl ring, and made a variety of N-aryl-N′-pyrazinylurea Chk1 inhibitors. Enzymatic activity less than 20 nM was observed in 15 of 41 compounds. Compound 8i provided the best overall results in the cellular assays as it abrogated doxorubicin-induced cell cycle arrest (IC50 = 1.7 μM) and enhanced doxorubicin cytotoxicity (IC50 = 0.44 μM) while displaying no single agent activity.
