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Baylor College of Medicine researchers hunt for a male contraception. 

Over the past 50 years, women have had the ability to choose from various forms of contraception best suited to their hormonal balances, body systems, and unique needs. However, men have not had the ability to do the same. Now the question remains, will men be able to control their own fertility one day?

“In the future, there should be a large number of opportunities, whether it’s for men or women, to have contraception." - Martin Matzuk, M.D., Ph.D., director, Center for Drug Discovery at Baylor College of Medicine, to Houston Matters on Houston Public Media radio in November 2015.

Research conducted within the Baylor College of Medicine labs of Drs. Matzuk and Lonard, are looking to pinpoint a protein or small molecule that can be translated into the derivation of a male contraceptive. Each lab is taking its own approach in developing a safe and effective method.

Dr. Matzuk’s lab is focused on targeting a small molecule that would only affect spermatogenesis, thereby inhibiting sperm function or motility. Dr. Lonard’s lab is concentrating on the reaction between small molecule inhibitors and steroid receptor coactivators into producing a non-hormonal male contraceptive. Here they describe their current research efforts in male contraception.

Martin Matzuk, M.D., Ph.D.

Dr. Martin Matzuk (320x240)
Martin Matzuk, M.D., Ph.D., director, Center for Drug Discovery, Stuart A. Wallace Chair and Professor, Department of Pathology and Immunology, Baylor College of Medicine, Director, Clinical Chemistry, Ben Taub Hospital

Although oral contraceptives have been available to women for the last 55 years, contraceptive choices for men (condoms and vasectomy) have been unchanged since World War II. One of the research goals of the Matzuk laboratory is to increase the contraceptives choices for men. Using the mouse as a model, Dr. Matzuk showed that oral contraceptives for males are possible.

In his groundbreaking work (Matzuk et al., Cell 2012), Dr. Matzuk demonstrated that the small molecule JQ1 reversibly inhibits the activity of the bromodomain testis-specific (BRDT) protein, preventing fertility in 100 percent of male mice that were administered the drug.

JQ1 demonstrates reversible male contraception with no effect on testosterone levels or changes in libido; however, JQ1 also targets other related bromodomain proteins expressed in tissues throughout the body. With his establishment of the Center for Drug Discovery at Baylor College of Medicine, Dr. Matzuk and his collaborators are working to find derivatives of JQ1 that will only interact with BRDT.

David Lonard, Ph.D.

Dr. David Lonard (320x240)
David Lonard, Ph.D, associate professor, Department of Molecular and Cellular Biology, Baylor College of Medicine

The Steroid Receptor Coactivators (SRC-1, SRC-2, and SRC-3) are master regulators for estrogen, progesterone, androgen, and other nuclear receptors and play key roles in the regulation of both the male and female reproductive systems. Specifically, SRC-2 is required for normal Sertoli cell function and SRC-2 knockout male mice become infertile shortly after the onset of puberty. This suggests that selective targeting of SRC-2 function in Sertoli cells could serve as a strategy to block sperm production.

Supporting this concept, it was found that the compound gossypol, which was already known as a male contraceptive agent, functions as a SRC-2 inhibitor. However, due to unacceptable side effects, gossypol was abandoned as a viable contraceptive agent. Dr. Lonard’s lab is engaged in the development of small molecule inhibitors (SMIs) against SRCs, including the development of SRC-2 SMIs for potential use as male contraceptive agents.

To identify new SRC-2 SMIs, we have executed a high throughput screening campaign of more than 400,000 compounds. These efforts have led to the identification of a number of promising lead compounds that can inhibit SRC-2 function at low nanomolar concentrations.

Currently, Dr. Lonard’s lab is actively engaged in medicinal chemistry efforts to improve the drug-like properties of these lead compounds and are evaluating them in cell culture and animal model systems. Steroid receptor coactivators function as pleiotropic transcriptional regulators that control metabolism and frequently drive cancer growth in addition to their roles in reproduction. Ultimately, it is expected that the SMIs that we develop against SRCs will find broad use for the treatment of cancer, metabolic disorders, and other disease states, in addition to potential as non-hormonal contraceptive agents.

This feature can be found in the spring 2016 CRM Newsletter