Emerging drug profile: cyclin-dependent kinase inhibitors

Abstract

As the rational application of targeted therapies in cancer supplants traditional cytotoxic chemotherapy, there is an ever-greater need for a thorough understanding of the complex machinery of the cell and an application of this knowledge to the development of novel therapeutics and combinations of agents. Here, we review the current state of knowledge of the class of targeted agents known as cyclin-dependent kinase (CDK) inhibitors, with a focus on chronic lymphocytic leukemia (CLL). Flavopiridol (alvocidib) is the best studied of the CDK inhibitors, producing a dramatic cytotoxic effect in vitro and in vivo, with the principal limiting factor of acute tumor lysis. Unfortunately, flavopiridol has a narrow therapeutic window and is relatively non-selective with several off-target (i.e. non-CDK) effects, which prompted development of the second-generation CDK inhibitor dinaciclib. Dinaciclib appears to be both more potent and selective than flavopiridol, with at least an order of magnitude greater therapeutic index, and is currently in phase III clinical trials. In additional to flavopiridol and dinaciclib, we also review the current status of other members of this class, and provide commentary as to the future direction of combination therapy including CDK inhibitors.

Keywords::

• Pharmacotherapeutics
• chemotherapeutic approaches
• cell cycle and apoptosis changes
• lymphoid leukemia
• lymphoma and Hodgkin disease

Potential conflict of interest:

Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.

This work was supported by the Specialized Center of Research from the Leukemia and Lymphoma Society, K12 CA133250, P50 CA140158 and P01 CA81534 from the National Cancer Institute, and The D. Warren Brown Foundation.