Three male and two female contraceptive drug discovery projects will be pursued, using state-of-the-art methods such as high throughput screening, structure-based drug design, and hit-to-lead optinnization by medicinal chemistry: 1. H2-Gamendazole (H2-GMZ) and Analogues of Narciclasine (NAR) for Male Contraception: The hypothesis of this project is that H2-GMZ and other small molecules such as NAR can be developed as reversible non-hormonal anti-spermatogenic contraceptive agents that reversibly disrupt eEFIA-actin bundling in Sertoli cells. 2. Retinoic Acid Receptor Alpha (RARalpha) as a Target for Male Contraception: Knockout models of RARa (Rara''') and animal experiments with a RAR pan-antagonist have validated RARalpha as a viable target for establishing reversible male infertility. The discovery of an alpha-selective RAR antagonist with good oral bioavailability is expected to provide a male contraceptive agent that has fewer unwanted side effects than existing pan-antagonists. 3. CATSPER as a Target for Male Contraception: The Cation channel of Sperm (CatSper) is involved in the regulation of intracellular calcium, an important component required for the initiation of sperm hypermotility during mammalian fertilization. Our working hypothesis is that inhibitors of CatSper will reduce sperm hypermotility by preventing Ca2+ influx and rendering sperm unable to successfully penetrate and fertilize the oocyte. 4. WEE2 Kinase as a Target for Female Contraception: Knockdown of WEE2 prevents fertilization of mature primate oocytes, indicating that WEE2 represents a promising target for the development of non-hormonal, gamete-specific contraceptive for women. 5. PDE3A as a Target for Female Contraception: The principal catabolic enzyme in the oocyte is phosphodiesterase 3A (PDE3A). Pharmacologic inhibitors of PDE3A block oocyte maturation in many species, including primates. These observations have led to the hypothesis that a selective PDE3A inhibitor could be developed as a female contraceptive agent.

Public Health Relevance

The availability of non-hormonal, orally bioavailable, safe, effective, and reversible contraceptive agents would be an important advance in expanding current contraceptive options available to couples. The discovery and development of a male non-hormonal contraceptive agent would finally provide men with a pharmacological agent for fertility control. Furthermore, since side effects prevent a significant number of women from using hormonal contraceptive agents, a non-hormonal method would be equally important to advance the contraceptive choices for women.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01HD076542-01
Application #
8530619
Study Section
Special Emphasis Panel (ZHD1-DRG-H (53))
Program Officer
Lee, Min S
Project Start
2012-09-24
Project End
2017-06-30
Budget Start
2012-09-24
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$888,430
Indirect Cost
$220,451
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Jakkaraj, Sudhakar; Young Jr, Victor G; Georg, Gunda I (2018) Syntheses of PDE3A inhibitor ORG9935 and determination of the absolute stereochemistries of its enantiomers by X-ray crystallography. Tetrahedron 74:2769-2774
Hawkinson, Jon E; Sinville, Rondedrick; Mudaliar, Deepti et al. (2017) Potent Pyrimidine and Pyrrolopyrimidine Inhibitors of Testis-Specific Serine/Threonine Kinase?2 (TSSK2). ChemMedChem 12:1857-1865
Ayoub, Alex M; Hawk, Laura M L; Herzig, Ryan J et al. (2017) BET Bromodomain Inhibitors with One-Step Synthesis Discovered from Virtual Screen. J Med Chem 60:4805-4817
Ember, Stuart W; Lambert, Que T; Berndt, Norbert et al. (2017) Potent Dual BET Bromodomain-Kinase Inhibitors as Value-Added Multitargeted Chemical Probes and Cancer Therapeutics. Mol Cancer Ther 16:1054-1067
Zhu, Jin-Yi; Cuellar, Rebecca A; Berndt, Norbert et al. (2017) Structural Basis of Wee Kinases Functionality and Inactivation by Diverse Small Molecule Inhibitors. J Med Chem 60:7863-7875
Shetty, Jagathpala; Sinville, Rondedrick; Shumilin, Igor A et al. (2016) Recombinant production of enzymatically active male contraceptive drug target hTSSK2 - Localization of the TSKS domain phosphorylated by TSSK2. Protein Expr Purif 121:88-96
Syeda, Shameem Sultana; Carlson, Erick J; Miller, Melissa R et al. (2016) The Fungal Sexual Pheromone Sirenin Activates the Human CatSper Channel Complex. ACS Chem Biol 11:452-9
Syeda, Shameem Sultana; Jakkaraj, Sudhakar; Georg, Gunda I (2015) Scalable syntheses of the BET bromodomain inhibitor JQ1. Tetrahedron Lett 56:3354-3457
Mishra, Neeraj K; Urick, Andrew K; Ember, Stuart W J et al. (2014) Fluorinated aromatic amino acids are sensitive 19F NMR probes for bromodomain-ligand interactions. ACS Chem Biol 9:2755-60
Ember, Stuart W J; Zhu, Jin-Yi; Olesen, Sanne H et al. (2014) Acetyl-lysine binding site of bromodomain-containing protein 4 (BRD4) interacts with diverse kinase inhibitors. ACS Chem Biol 9:1160-71

Showing the most recent 10 out of 12 publications