Review of rationale and progress toward targeting cyclin-dependent kinase 2 (CDK2) for male contraception

Erik B. Faber, Nan Wang, Gunda I. Georg

Research output: Contribution to journalArticlepeer-review

Abstract

Cyclin-dependent kinase 2 (CDK2) is a member of the larger cell cycle regulating CDK family of kinases, activated by binding partner cyclins as its name suggests. Despite its canonical role in mitosis, CDK2 knockout mice are viable but sterile, suggesting compensatory mechanisms for loss of CDK2 in mitosis but not meiosis. Here, we review the literature surrounding the role of CDK2 in meiosis, particularly a cyclin-independent role in complex with another activator, Speedy 1 (SPY1). From this evidence, we suggest that CDK2 could be a viable nonhormonal male contraceptive target. Finally, we review the literature of pertinent CDK2 inhibitors from the preclinical to clinical stages, mostly developed to treat various cancers. To date, there is no potent yet selective CDK2 inhibitor that could be repurposed as a contraceptive without appreciable off-target toxicity. To achieve selectivity for CDK2 over closely related kinases, developing compounds that bind outside the conserved adenosine triphosphate-binding site may be necessary.

Original languageEnglish (US)
Pages (from-to)357-367
Number of pages11
JournalBiology of reproduction
Volume103
Issue number2
DOIs
StatePublished - Aug 1 2020

Bibliographical note

Funding Information:
*Correspondence: Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota–Twin Cities, 717 Delaware St. SE, Room 451, Minneapolis, MN 55414, USA. Tel: +1-612-626-6320; E-mail: georg@umn.edu †Grant Support: This work was supported by NIH/NICHD 5 U01 HD080431, NIH/NICHD 1 R61 HD099743, and NIH/NIGMS R01 GM121515. E. Faber was supported by NIH/NIGMS training grants T32 GM008244 and T32 GM008700 as well as by NIH/NCI fellowship F30 CA232303. Erik B. Faber and Nan Wang contributed equally to this work.

Keywords

  • Contraception
  • Kinases
  • Male reproductive tract
  • Meiosis
  • Meiotic arrest
  • Spermatogenesis

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