2. Academic Validation
  3. Screening through Lead Optimization of High Affinity, Allosteric Cyclin-Dependent Kinase 2 (CDK2) Inhibitors as Male Contraceptives That Reduce Sperm Counts in Mice

Screening through Lead Optimization of High Affinity, Allosteric Cyclin-Dependent Kinase 2 (CDK2) Inhibitors as Male Contraceptives That Reduce Sperm Counts in Mice

  • J Med Chem. 2023 Feb 9;66(3):1928-1940. doi: 10.1021/acs.jmedchem.2c01731.
Erik B Faber 1 2,  Nan Wang 1,  Kristen John 1,  Luxin Sun 3,  Henry L Wong 1,  David Burban 4,  Rawle Francis 1,  Defeng Tian 1,  Kwon H Hong 1,  An Yang 1,  Liming Wang 1,  Mazen Elsaid 1,  Hira Khalid 1,  Nicholas M Levinson 4,  Ernst Schönbrunn 3,  Jon E Hawkinson 1,  Gunda I Georg 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, University of Minnesota College of Pharmacy─Twin Cities, Minneapolis, Minnesota55414, United States.
  • 2 Medical Scientist Training Program, University of Minnesota Medical School─Twin Cities, Minneapolis, Minnesota55455, United States.
  • 3 Drug Discovery Department, Moffitt Cancer Center, Tampa, Florida33612, United States.
  • 4 Department of Pharmacology, University of Minnesota Medical School─Twin Cities, Minneapolis, Minnesota55455, United States.
PMID: 36701569 DOI: 10.1021/acs.jmedchem.2c01731
Abstract

Although cyclin-dependent kinase 2 (CDK2) is a validated target for both Cancer and contraception, developing a CDK2 Inhibitor with exquisite selectivity has been challenging due to the structural similarity of the ATP-binding site, where most kinase inhibitors bind. We previously discovered an allosteric pocket in CDK2 with the potential to bind a selective compound and then discovered and structurally confirmed an anthranilic acid scaffold that binds this pocket with high affinity. These allosteric inhibitors are selective for CDK2 over structurally similar CDK1 and show contraceptive potential. Herein, we describe the screening and optimization that led to compounds like EF-4-177 with nanomolar affinity for CDK2. EF-4-177 is metabolically stable, orally bioavailable, and significantly disrupts spermatogenesis, demonstrating this series' therapeutic potential. This work details the discovery of the highest affinity allosteric CDK inhibitors reported and shows promise for this series to yield an efficacious and selective allosteric CDK2 Inhibitor.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-161690
    CDK2抑制剂
    CDK
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