Whether to target single or multiple CDKs for therapy? That is the question.
Complexes consisting of cyclin-dependent kinases (CDKs) and their regulatory subunits (the cyclins) control the progression of normal mammalian cells through the cell cycle. However, during malignant transformation this regulatory apparatus malfunctions, allowing cells to undergo unchecked proliferation. In many cases, the high mitotic potential of malignant cells is due to the constitutive activation of CDK-cyclin complexes, facilitated by the inactivation of cellular CDK inhibitors, such as p16(INK4A) or p27(Kip1), and the loss of functional tumor suppressors, such as the p53 and pRb proteins. It has recently been suggested that pharmacological intervention based on remedying the deficiency or loss of activity of these negative regulators of the cell cycle could be a very effective therapeutic option in the treatment of cancer. Multiple CDK inhibitors have been synthesized over the last two decades, spanning at least five classes of compounds. While these inhibitors can be classified on the basis of their chemical structure, it may be more interesting to categorize them according to their pharmacological nature, as broad-spectrum unspecific, pan-specific, or very selective antagonists. This review offers a critical assessment of the advantages and disadvantages of both pan-specific and highly selective CDK inhibitors in therapy.
Węsierska-Gądek
Józefa
J
Cell Cycle Regulation Group, Div., Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, Vienna, Austria. Jozefa.Gadek-Wesierski@meduniwien.ac.at
Maurer
Margarita
M
Zulehner
Nora
N
Komina
Oxana
O
D002453:Cell Cycle / Q000502:physiology; D002986:Clinical Trials as Topic; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000378:metabolism / Q000627:therapeutic use; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D021122:Protein Subunits / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D016213:Cyclins; D047428:Protein Kinase Inhibitors; D021122:Protein Subunits; D025521:Tumor Suppressor Proteins; D018844:Cyclin-Dependent Kinases