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Research Articles: Therapeutics, Targets, and Development

In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor, P276-00

¹ Department of Pharmacology, ² Department of Medicinal Chemistry, Nicholas Piramal Research Centre, Nicholas Piramal India Limited, 1-Nirlon Complex, Goregaon, Mumbai, India

Requests for reprints: Kalpana S. Joshi, Department of Pharmacology, Nicholas Piramal Research Center, Nicholas Piramal India Limited, 1-Nirlon Complex, Goregaon (E), Mumbai 400 063, India. Phone: 91-22-3081-8421; Fax: 91-22-3081-8411; E-mail; kjoshi{at}nicholaspiramal.co.in

Abstract

Cyclin-dependent kinases (Cdk) and their associated pathways represent some of the most attractive targets for the development of anticancer therapeutics. Based on antitumor activity in animal models, a variety of Cdk inhibitors are undergoing clinical evaluation either as a single agent or in combination with other approved drugs. In our anticancer drug discovery program, a novel series of flavones have been synthesized for evaluation against the activity of Cdk4-D1. This enzyme catalyzes the phosphorylation of retinoblastoma protein, thus inhibiting its function. We have identified a series of potent Cdk4-D1 inhibitors with IC₅₀ below 250 nmol/L. In this report, we have described the properties of one of the best compound, P276-00 of the flavone's series. P276-00 shows 40-fold selectivity toward Cdk4-D1, compared with Cdk2-E. The specificity toward 14 other related and unrelated kinases was also determined. P276-00 was found to be more selective with IC₅₀s <100 nmol/L for Cdk4-D1, Cdk1-B, and Cdk9-T1, as compared with other Cdks, and less selective for non-Cdk kinases. It showed potent antiproliferative effects against various human cancer cell lines, with an IC₅₀ ranging from 300 to 800 nmol/L and was further compared for its antiproliferative activity against cancer and normal fibroblast cell lines. P276-00 was found to be highly selective for cancer cells as compared with normal fibroblast cells. To delineate its mechanism of action, the effect of P276-00 on cell cycle proteins was studied in human breast cancer cell line (MCF-7) and human non–small cell lung carcinoma (H-460). A significant down-regulation of cyclin D1 and Cdk4 and a decrease in Cdk4-specific pRb Ser⁷⁸⁰ phosphorylation was observed. P276-00 produced potent inhibition of Cdk4-D1 activity that was found to be competitive with ATP and not with retinoblastoma protein. The compound also induced apoptosis in human promyelocytic leukemia (HL-60) cells, as evidenced by the induction of caspase-3 and DNA ladder studies. These data suggest that P276-00 has the potential to be developed as an anti-Cdk chemotherapeutic agent. [Mol Cancer Ther 2007;6(3):918–25]

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Received 10/ 4/06; revised 12/ 4/06; accepted 2/ 1/07.