The Steroid Receptor Coactivators are master regulators of nuclear receptors. Specifically, SRC-2 serves as a regulator of male reproduction and is preferentially expressed in Sertoli cells. SRC-2'^'males are able to produce sperm at tlie onset of pulserty, but quickly become infertile. This loss of male fertility is due to defects in Sertoli cell function which raises the possibility that effective anti-SRC-2 small molecule antagonists (SMAs) can be developed as male contraceptive agents. Gossypol was tested as a male contraceptive agent in ~10,000 men in China and was found to be well tolerated at the doses tested and was effective as an anti-fertility agent 99% of the time. However, due to the risic of inreversible infertility and hyperkalemia, its use as a contraceptive agent was abandoned. Interestingly, gossypol treated animals develop defects in Sertoli cell biology that are strikingly similar to that seen in SRC-2'''mice. Genetic disruption of SRC-2 and gossypol treatment both result in teratozoospermia and age dependent-iike testicular degeneration. Sertoli cells of both SRC-2'''and gossypol-treated mice accumulate lipid, indicative of a common defect in Sertoli cell metabolism. In preliminary screening for SRC-2 SMIs in our laboratory, we have identified several gossypol derivatives that can disrupt the coactivator function of SRC-2. We have already completed high throughput screening campaigns for SMAs against SRC-1 and SRC-3 and are initiating a similar effort for SRC-2 as well. Because of the strong link between SRC-2, gossypol, Sertoli cell biology and male infertility, we propose to screen and characterize new SRC-2 S M ^ as a novel class of male contraceptive agents. In conjunction with support for compound chemistry that exists in this U54 application, we expect to generate SRC-2-targeting male contraceptive agents with the potential to be clinically viable.

Public Health Relevance

Small molecule antagonist screens to identify agents that can dismpt the function of steroid receptor coactivator 2 have identified a number of gossypol derivates as tool compounds. Because gossypol is a male anti-fertility agent that disrupts Sertoli cell function and produces effects that phenocopy defects in male reproduction observed in SRC-2'''mice, this proposal aims to develop a new class of male contraceptive agents, based on their ability to target SRC-2.

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 #
5U01HD076596-02
Application #
8546441
Study Section
Special Emphasis Panel (ZHD1-DRG-H (53))
Program Officer
Lee, Min S
Project Start
2012-08-24
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$207,926
Indirect Cost
$75,066
Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Wang, Ying; Lonard, David M; Yu, Yang et al. (2014) Bufalin is a potent small-molecule inhibitor of the steroid receptor coactivators SRC-3 and SRC-1. Cancer Res 74:1506-17
Yan, Fei; Yu, Yang; Chow, Dar-Chone et al. (2014) Identification of verrucarin a as a potent and selective steroid receptor coactivator-3 small molecule inhibitor. PLoS One 9:e95243