Emerging Drug Profile: Cyclin-Dependent Kinase Inhibitors
Authors
James MD
Division of Hematology, Department of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus Ohio
John MD
Division of Hematology, Department of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus Ohio
Keywords:
Pharmacotherapeutics, Chemotherapeutic approaches, Cell cycle and apoptosis changes, Lymphoid Leukemia, Lymphoma and Hodgkin disease
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 state 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
Author Biographies
James MD
, Division of Hematology, Department of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus Ohio
Division of Oncology, Department of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus Ohio
John MD
, Division of Hematology, Department of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus Ohio
Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus Ohio
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