Small Molecule Male Contraceptive Found to Be Safe and Reversible in Mouse Model

A prototype orally administered male contraceptive based on a small molecule that prevents sperm development was tested successfully in a mouse model.

The drug called JQ1 was found to inhibit reversibly the action of bromodomain, testis-specific (BRDT), a protein required by the testis for sperm development. A bromodomain is a protein domain that recognizes acetylated lysine residues such as those on the N-terminal tails of histones. This recognition is often a prerequisite for protein-histone association and chromatin remodeling. Thus, the bromodomain is found in proteins that regulate transcription.

JQ1 was fabricated at Harvard Medical School (Boston, MA, USA) while experiments in mice were carried out at Baylor College of Medicine (Houston, TX, USA).

The investigators reported in the August 17, 2012, issue of the journal Cell that JQ1 was a potent inhibitor of BRDT, which is essential for chromatin remodeling during spermatogenesis. Biochemical and crystallographic studies confirmed that occupancy of the BRDT acetyl-lysine binding pocket by JQ1 prevented recognition of acetylated histone H4.

Treatment of mice with JQ1 reduced seminiferous tubule area, testis size, and spermatozoa number and motility without affecting hormone levels. Although JQ1-treated males mated normally, inhibitory effects of JQ1 evident at the spermatocyte and round spermatid stages caused a complete and reversible contraceptive effect.

"We found that the JQ1 molecule causes a contraceptive effect in males," said first author Dr. Martin M. Matzuk, professor of molecular biology, molecular and human genetics, and pharmacology at Baylor College of Medicine. "If you stop the drug, there is complete reversibility. JQ1 is not the pill for men, because it also binds other members of the bromodomain family. However, the data is proof of principle that BRDT is an excellent target for male contraception and provides us with useful information for future drug development."

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Harvard Medical School
Baylor College of Medicine