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Pyrido[2,3-d]pyrimidin-7-ones as specific inhibitors of cyclin-dependent kinase 4.

Abstract：

:Inhibition of the cell cycle kinase, cyclin-dependent kinase-4 (Cdk4), is expected to provide an effective method for the treatment of proliferative diseases such as cancer. The pyrido[2,3-d]pyrimidin-7-one template has been identified previously as a privileged structure for the inhibition of ATP-dependent kinases, and good potency against Cdks has been reported for representative examples. Obtaining selectivity for individual Cdk enzymes, particularly Cdk4, has been challenging. Here, we report that the introduction of a methyl substituent at the C-5 position of the pyrido[2,3-d]pyrimidin-7-one template is sufficient to confer excellent selectivity for Cdk4 vs other Cdks and representative tyrosine kinases. Further optimization led to the identification of highly potent and selective inhibitors of Cdk4 that exhibit potent antiproliferative activity against human tumor cells in vitro. The most selective Cdk4 inhibitors were evaluated for antitumor activity against MDA-MB-435 human breast carcinoma xenografts in mice.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

VanderWel SN,Harvey PJ,McNamara DJ,Repine JT,Keller PR,Quin J 3rd,Booth RJ,Elliott WL,Dobrusin EM,Fry DW,Toogood PL

doi

10.1021/jm049355+

keywords:

subject

Has Abstract

pub_date

2005-04-07 00:00:00

pages

2371-87

issue

7

eissn

0022-2623

issn

1520-4804

journal_volume

48

pub_type

杂志文章

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