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.