Synthesis and biological evaluation of 1-(2,4,5-trisubstituted phenyl)-3-(5-cyanopyrazin-2-yl)ureas as potent Chk1 kinase inhibitors.
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 microM) and enhanced doxorubicin cytotoxicity (IC50=0.44 microM) while displaying no single agent activity.
Li
Gaoquan
G
Cancer Research, Global Pharmaceutical Research & Development, Abbott Laboratories, Abbott Park, IL 60064, USA. Gaoquan.Li@abbott.com
Hasvold
Lisa A
LA
Tao
Zhi-Fu
ZF
Wang
Gary T
GT
Gwaltney
Stephen L
SL
Patel
Jyoti
J
Kovar
Peter
P
Credo
Robert B
RB
Chen
Zehan
Z
Zhang
Haiying
H
Park
Chang
C
Sham
Hing L
HL
Sowin
Thomas
T
Rosenberg
Saul H
SH
Lin
Nan-Horng
NH
D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D000071877:Checkpoint Kinase 1; D018360:Crystallography, X-Ray; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D009570:Nitriles / Q000138:chemical synthesis / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D011494:Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D011719:Pyrazines / Q000138:chemical synthesis / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D004317:Doxorubicin; D014508:Urea; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1