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Molecular Pharmacology

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Rapid CommunicationMinireview

Cyclin-Dependent Kinase Inhibitors as Anticancer Therapeutics

Mary E. Law, Patrick E. Corsino, Satya Narayan and Brian K. Law
Molecular Pharmacology November 2015, 88 (5) 846-852; DOI: https://doi.org/10.1124/mol.115.099325
Mary E. Law
Departments of Pharmacology and Therapeutics (M.E.L., P.E.C., B.K.L.), Anatomy and Cell Biology (S.N.), and the University of Florida Health Cancer Center (M.E.L., P.E.C., S.N., B.K.L.), University of Florida, Gainesville, Florida
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Patrick E. Corsino
Departments of Pharmacology and Therapeutics (M.E.L., P.E.C., B.K.L.), Anatomy and Cell Biology (S.N.), and the University of Florida Health Cancer Center (M.E.L., P.E.C., S.N., B.K.L.), University of Florida, Gainesville, Florida
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Satya Narayan
Departments of Pharmacology and Therapeutics (M.E.L., P.E.C., B.K.L.), Anatomy and Cell Biology (S.N.), and the University of Florida Health Cancer Center (M.E.L., P.E.C., S.N., B.K.L.), University of Florida, Gainesville, Florida
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Brian K. Law
Departments of Pharmacology and Therapeutics (M.E.L., P.E.C., B.K.L.), Anatomy and Cell Biology (S.N.), and the University of Florida Health Cancer Center (M.E.L., P.E.C., S.N., B.K.L.), University of Florida, Gainesville, Florida
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Abstract

Cyclin-dependent kinases (CDKs) have been considered promising drug targets for a number of years, but most CDK inhibitors have failed rigorous clinical testing. Recent studies demonstrating clear anticancer efficacy and reduced toxicity of CDK4/6 inhibitors such as palbociclib and multi-CDK inhibitors such as dinaciclib have rejuvenated the field. Favorable results with palbociclib and its recent U.S. Food and Drug Administration approval demonstrate that CDK inhibitors with narrow selectivity profiles can have clinical utility for therapy based on individual tumor genetics. A brief overview of results obtained with ATP-competitive inhibitors such as palbociclib and dinaciclib is presented, followed by a compilation of new avenues that have been pursued toward the development of novel, non–ATP-competitive CDK inhibitors. These creative ways to develop CDK inhibitors are presented along with crystal structures of these agents complexed with CDK2 to highlight differences in their binding sites and mechanisms of action. The recent successes of CDK inhibitors in the clinic, combined with the potential for structure-based routes to the development of non–ATP-competitive CDK inhibitors, and evidence that CDK inhibitors may have use in suppressing chromosomal instability and in synthetic lethal drug combinations inspire optimism that CDK inhibitors will become important weapons in the fight against cancer.

Footnotes

    • Received April 2, 2015.
    • Accepted May 27, 2015.
  • This work was supported, in whole or in part, by the National Institutes of Health [Grant R01-CA93651]. This work was also supported by the Florida Department of Health [Grants 07BB-8 and 09BB-10], Susan G. Komen for the Cure [Grant KG080510], and Florida Department of Health [Grant 08BB-05].

  • dx.doi.org/10.1124/mol.115.099325.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 88 (5)
Molecular Pharmacology
Vol. 88, Issue 5
1 Nov 2015
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Rapid CommunicationMinireview

CDK Inhibitors as Anticancer Therapeutics

Mary E. Law, Patrick E. Corsino, Satya Narayan and Brian K. Law
Molecular Pharmacology November 1, 2015, 88 (5) 846-852; DOI: https://doi.org/10.1124/mol.115.099325

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Rapid CommunicationMinireview

CDK Inhibitors as Anticancer Therapeutics

Mary E. Law, Patrick E. Corsino, Satya Narayan and Brian K. Law
Molecular Pharmacology November 1, 2015, 88 (5) 846-852; DOI: https://doi.org/10.1124/mol.115.099325
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  • Article
    • Abstract
    • Introduction
    • Pivotal Discoveries Leading to Our Current Understanding of the Cell Cycle
    • Rationales for and against CDK Inhibitors as Anticancer Therapeutics
    • Pan-CDK Inhibitors
    • CDK4/6-Selective Compounds
    • Non–Cell Cycle CDKs as Drug Targets
    • Creative Approaches to CDK Inhibition
    • What is the Goal: Proliferative Arrest? Senescence? Cell Death? Suppression of Chromosomal Instability?
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