Small-molecule inhibition of BRDT for male contraception.
A pharmacologic approach to male contraception remains a longstanding challenge in medicine. Toward this objective, we explored the spermatogenic effects of a selective small-molecule inhibitor (JQ1) of the bromodomain and extraterminal (BET) subfamily of epigenetic reader proteins. Here, we report potent inhibition of the testis-specific member BRDT, which is essential for chromatin remodeling during spermatogenesis. Biochemical and crystallographic studies confirm that occupancy of the BRDT acetyl-lysine binding pocket by JQ1 prevents 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 mate normally, inhibitory effects of JQ1 evident at the spermatocyte and round spermatid stages cause a complete and reversible contraceptive effect. These data establish a new contraceptive that can cross the blood:testis boundary and inhibit bromodomain activity during spermatogenesis, providing a lead compound targeting the male germ cell for contraception.
Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA. mmatzuk@bcm.edu
Martin M
MM
Matzuk
Michael R
MR
McKeown
Panagis
P
Filippakopoulos
Qinglei
Q
Li
Lang
L
Ma
Julio E
JE
Agno
Madeleine E
ME
Lemieux
Sarah
S
Picaud
Richard N
RN
Yu
Jun
J
Qi
Stefan
S
Knapp
James E
JE
Bradner
D000818:Animals; D001381:Azepines / Q000737:chemistry / Q000494:pharmacology*; D001814:Blood-Testis Barrier; D003272:Contraceptive Agents, Male / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D017434:Protein Structure, Tertiary; D013076:Sperm Count; D013081:Sperm Motility / Q000187:drug effects; D013094:Spermatozoa / Q000187:drug effects; D013737:Testis / Q000166:cytology / Q000187:drug effects; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*; D000092468:Bromodomain Containing Proteins
D001381:Azepines; D003272:Contraceptive Agents, Male; D009687:Nuclear Proteins; D014230:Triazoles; C561695:(+)-JQ1 compound; C109570:BRDT protein, human; D000092468:Bromodomain Containing Proteins; C518475:BRDT protein, mouse