Small molecule inhibitors targeting cyclin-dependent kinases as anticancer agents

被引：46

作者：

Dai Y. ^{[1
]}

Grant S. ^{[1
]}

机构：

[1] Division of Hematology/Oncology, Virginia Commonwealth University, Medical College of Virginia, Richmond, VA 23298

来源：

Current Oncology Reports | 2004年 / 6卷 / 2期

基金：

美国国家卫生研究院;

关键词：

Breast Cancer Resistance Protein; Human Leukemia Cell; Flavopiridol; SU9516; Indirubin;

D O I：

10.1007/s11912-004-0024-3

中图分类号：

学科分类号：

摘要：

Cyclin-dependent kinases (CDKs) and their related pathways represent some of the most attractive targets in the development of anticancer therapeutics. Among a variety of CDK inhibitors under development, flavopiridol, UCN-01, CYC202, and BMS-387032 are undergoing clinical evaluation based on evidence of preclinical antitumor activity. Flavopiridol exerts multiple effects in tumor cells, including inhibition of multiple CDKs, transcriptional inhibition secondary to disruption of P-TEFb (CDK9/cyclin T), induction of apoptosis, and antiangiogenesis. UCN-01 was initially developed as a protein kinase C (PKC) inhibitor, but its major antitumor effects appear to be related to CDK inhibition or "inappropriate" activation of cdc2/CDK1 abrogating the G2 and S checkpoints, inhibition of PDK1/Akt, and induction of apoptosis through a PKC-independent mechanism. Significantly, combining these CDK inhibitors with either conventional cytotoxic drugs or novel agents targeting signal transduction pathways can markedly enhance antitumor activity, particularly induction of apoptosis, in various preclinical models. Such findings may serve as a basis for the introduction of novel combination regimens into clinical trials. Copyright © 2004 by Current Science Inc.

引用

页码：123 / 130

页数：7

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