EK-6136 (3-methyl-4-(O-methyl-oximino)-1-phenylpyrazolin-5-one): a novel Cdc25B inhibitor with antiproliferative activity.
Cdc25B is a dual specific phosphatase, which plays a pivotal role in the activation of cell-cycle-dependent kinase 1 (Cdk1). A novel Cdc25B inhibitor, EK-6136, was identified by high throughput screening (HTS) using compounds from Korea Chemical Bank and examined for its biological effects. EK-6136 inhibited Cdc25B with an IC50 of 6.4+/-1.5 microM. EK-6136 showed selectivity against several phosphatases including PTP-1B, CD45, Cdc25A, PP1, VHR and Yop. In the inhibition kinetic study, EK-6136 displayed a mixed inhibition pattern with a Ki value of 7.8+/-1.2 microM. Consistent with in vitro results, EK-6136 inhibited the proliferation of MCF-7 (human breast carcinoma), HT-29 (human colorectal adenocarcinoma) and A549 (lung carcinoma) cells with increased Cdk-1 phosphorylation. Herein, we propose that EK-6136 is an active HTS hit as a Cdc25B inhibitor with antiproliferative activity, and can be used for the design of more potent and selective antiproliferative agents.
Kim
Kwang-Rok
KR
Laboratory of Molecular Pharmacology and Physiology, Medicinal Science Division, Korea Research Institute of Chemical Technology, Jang-Dong 100, Yusung-Gu, TaeJon 305-343, South Korea.
Kwon
Ju-Lee
JL
Kim
Ji-Sun
JS
No
Zaesung
Z
Kim
Hyoung Rae
HR
Cheon
Hyae Gyeong
HG
D016203:CDC2 Protein Kinase / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019073:HT29 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D047069:Pyrazolones / Q000494:pharmacology*; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors*
C508437:3-methyl-4-(O-methyl-oximino)-1-phenylpyrazolin-5-one; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D047069:Pyrazolones; D016203:CDC2 Protein Kinase; C517004:CDC25A protein, human; C517008:CDC25B protein, human; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D020687:cdc25 Phosphatases