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Small-molecule inhibition of BRDT for male contraception.

Matzuk MM, McKeown MR, Filippakopoulos P, Li Q, Ma L, Agno JE, Lemieux ME, Picaud S, Yu RN, Qi J, Knapp S, Bradner JE - Cell (2012)

Bottom Line: 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.Biochemical and crystallographic studies confirm that occupancy of the BRDT acetyl-lysine binding pocket by JQ1 prevents recognition of acetylated histone H4.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA. mmatzuk@bcm.edu

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Related in: MedlinePlus

BRDT Inhibition with a Testis-Permeable Small Molecule Reduces Testis Size and Sperm Counts and Motility(A) Pharmacokinetic analysis of JQ1 in plasma (black lines) and testis (red lines) following a single administration of JQ1 (50 mg/kg IP) to male mice. Data represent the mean ± SD.(B) Gross analysis of testes from 9-week-old mice that received control or JQ1 (50 mg/kg daily) for 3 weeks.(C) Testis weights from mice treated with control or JQ1 (50 mg/kg QD) for 3–6 weeks, 6–9 weeks, or 6–12 weeks of age. Data represent the mean ± SEM and are annotated with P values obtained from a two-tailed t test (∗p < 0.05).(D) Graphical representation of sperm counts obtained from the entire epididymides of males treated with JQ1 or control from 6–9 weeks of age or the tail of the epididymis of males treated from 6–12 weeks of age with vehicle or JQ1 (50 mg/kg QD). Data represent the mean ± SEM (∗p < 0.05).(E) Motility of mature sperm obtained from the cauda epididymis of adult males treated with JQ1 (50 mg/kg daily) from 6–12 weeks of age. Data represent the mean ± SEM (∗p < 0.0001).(F) Pharmacokinetic analysis of JQ1 in plasma (black lines) and testis (red lines) following twice-daily (BID) administration of JQ1 (50 mg/kg IP) to male mice. Data represent the mean ± SD.(G) Testis weights (mg) from mice treated with control or JQ1 (50 mg/kg BID) from 9–12 weeks of age. Data represent the mean ± SEM (∗p < 0.05).(H) Sperm counts obtained from the cauda epididymis of males treated from 9–12 weeks of age with vehicle or JQ1 (50 mg/kg BID). Data represent the mean ± SEM (∗p < 0.05).(I) Motility of mature sperm obtained from the cauda epididymis of adult males treated with JQ1 (50 mg/kg BID) or vehicle from 9–12 weeks. Data represent the mean ± SEM (∗p < 0.001).(J) Cross-sectional area of seminiferous tubules from JQ1-treated mice (50 mg/kg QD for 3–6 weeks or 6–12 weeks, or 50 mg/kg BID for 9–12 weeks, as shown) or control (∗p < 0.05).(K, L, and M) Male mice treated with JQ1 or vehicle from 6–12 weeks exhibit statistically similar serum levels of (K) testosterone, (L) luteinizing hormone (LH), and (M) follicle-stimulating hormone (FSH).See also Figure S1 and Tables S3 and S4.
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fig3: BRDT Inhibition with a Testis-Permeable Small Molecule Reduces Testis Size and Sperm Counts and Motility(A) Pharmacokinetic analysis of JQ1 in plasma (black lines) and testis (red lines) following a single administration of JQ1 (50 mg/kg IP) to male mice. Data represent the mean ± SD.(B) Gross analysis of testes from 9-week-old mice that received control or JQ1 (50 mg/kg daily) for 3 weeks.(C) Testis weights from mice treated with control or JQ1 (50 mg/kg QD) for 3–6 weeks, 6–9 weeks, or 6–12 weeks of age. Data represent the mean ± SEM and are annotated with P values obtained from a two-tailed t test (∗p < 0.05).(D) Graphical representation of sperm counts obtained from the entire epididymides of males treated with JQ1 or control from 6–9 weeks of age or the tail of the epididymis of males treated from 6–12 weeks of age with vehicle or JQ1 (50 mg/kg QD). Data represent the mean ± SEM (∗p < 0.05).(E) Motility of mature sperm obtained from the cauda epididymis of adult males treated with JQ1 (50 mg/kg daily) from 6–12 weeks of age. Data represent the mean ± SEM (∗p < 0.0001).(F) Pharmacokinetic analysis of JQ1 in plasma (black lines) and testis (red lines) following twice-daily (BID) administration of JQ1 (50 mg/kg IP) to male mice. Data represent the mean ± SD.(G) Testis weights (mg) from mice treated with control or JQ1 (50 mg/kg BID) from 9–12 weeks of age. Data represent the mean ± SEM (∗p < 0.05).(H) Sperm counts obtained from the cauda epididymis of males treated from 9–12 weeks of age with vehicle or JQ1 (50 mg/kg BID). Data represent the mean ± SEM (∗p < 0.05).(I) Motility of mature sperm obtained from the cauda epididymis of adult males treated with JQ1 (50 mg/kg BID) or vehicle from 9–12 weeks. Data represent the mean ± SEM (∗p < 0.001).(J) Cross-sectional area of seminiferous tubules from JQ1-treated mice (50 mg/kg QD for 3–6 weeks or 6–12 weeks, or 50 mg/kg BID for 9–12 weeks, as shown) or control (∗p < 0.05).(K, L, and M) Male mice treated with JQ1 or vehicle from 6–12 weeks exhibit statistically similar serum levels of (K) testosterone, (L) luteinizing hormone (LH), and (M) follicle-stimulating hormone (FSH).See also Figure S1 and Tables S3 and S4.

Mentions: To test the ability of JQ1 to reach its contraceptive target cells, the testicular bioavailability of JQ1 was assessed by serum and tissue pharmacokinetic analysis. Following a single intraperitoneal (i.p.) dose of JQ1 (50 mg/kg) in male mice, measurements of JQ1 concentration were made in serum, testis, and brain (Figure 3A and Table S3). Overall, JQ1 exhibits excellent testicular bioavailability (AUCtestis/AUCplasma = 259%), suggesting preferential distribution into this tissue compartment with rapid (Tmax = 0.25 hr) and pronounced exposure (Cmax = 34 μg/ml). Corroborating barrier permeability by JQ1, nearly uniform blood-brain barrier permeability was observed after single-dose pharmacokinetic studies (AUCbrain/AUCplasma = 98%).


Small-molecule inhibition of BRDT for male contraception.

Matzuk MM, McKeown MR, Filippakopoulos P, Li Q, Ma L, Agno JE, Lemieux ME, Picaud S, Yu RN, Qi J, Knapp S, Bradner JE - Cell (2012)

BRDT Inhibition with a Testis-Permeable Small Molecule Reduces Testis Size and Sperm Counts and Motility(A) Pharmacokinetic analysis of JQ1 in plasma (black lines) and testis (red lines) following a single administration of JQ1 (50 mg/kg IP) to male mice. Data represent the mean ± SD.(B) Gross analysis of testes from 9-week-old mice that received control or JQ1 (50 mg/kg daily) for 3 weeks.(C) Testis weights from mice treated with control or JQ1 (50 mg/kg QD) for 3–6 weeks, 6–9 weeks, or 6–12 weeks of age. Data represent the mean ± SEM and are annotated with P values obtained from a two-tailed t test (∗p < 0.05).(D) Graphical representation of sperm counts obtained from the entire epididymides of males treated with JQ1 or control from 6–9 weeks of age or the tail of the epididymis of males treated from 6–12 weeks of age with vehicle or JQ1 (50 mg/kg QD). Data represent the mean ± SEM (∗p < 0.05).(E) Motility of mature sperm obtained from the cauda epididymis of adult males treated with JQ1 (50 mg/kg daily) from 6–12 weeks of age. Data represent the mean ± SEM (∗p < 0.0001).(F) Pharmacokinetic analysis of JQ1 in plasma (black lines) and testis (red lines) following twice-daily (BID) administration of JQ1 (50 mg/kg IP) to male mice. Data represent the mean ± SD.(G) Testis weights (mg) from mice treated with control or JQ1 (50 mg/kg BID) from 9–12 weeks of age. Data represent the mean ± SEM (∗p < 0.05).(H) Sperm counts obtained from the cauda epididymis of males treated from 9–12 weeks of age with vehicle or JQ1 (50 mg/kg BID). Data represent the mean ± SEM (∗p < 0.05).(I) Motility of mature sperm obtained from the cauda epididymis of adult males treated with JQ1 (50 mg/kg BID) or vehicle from 9–12 weeks. Data represent the mean ± SEM (∗p < 0.001).(J) Cross-sectional area of seminiferous tubules from JQ1-treated mice (50 mg/kg QD for 3–6 weeks or 6–12 weeks, or 50 mg/kg BID for 9–12 weeks, as shown) or control (∗p < 0.05).(K, L, and M) Male mice treated with JQ1 or vehicle from 6–12 weeks exhibit statistically similar serum levels of (K) testosterone, (L) luteinizing hormone (LH), and (M) follicle-stimulating hormone (FSH).See also Figure S1 and Tables S3 and S4.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3420011&req=5

fig3: BRDT Inhibition with a Testis-Permeable Small Molecule Reduces Testis Size and Sperm Counts and Motility(A) Pharmacokinetic analysis of JQ1 in plasma (black lines) and testis (red lines) following a single administration of JQ1 (50 mg/kg IP) to male mice. Data represent the mean ± SD.(B) Gross analysis of testes from 9-week-old mice that received control or JQ1 (50 mg/kg daily) for 3 weeks.(C) Testis weights from mice treated with control or JQ1 (50 mg/kg QD) for 3–6 weeks, 6–9 weeks, or 6–12 weeks of age. Data represent the mean ± SEM and are annotated with P values obtained from a two-tailed t test (∗p < 0.05).(D) Graphical representation of sperm counts obtained from the entire epididymides of males treated with JQ1 or control from 6–9 weeks of age or the tail of the epididymis of males treated from 6–12 weeks of age with vehicle or JQ1 (50 mg/kg QD). Data represent the mean ± SEM (∗p < 0.05).(E) Motility of mature sperm obtained from the cauda epididymis of adult males treated with JQ1 (50 mg/kg daily) from 6–12 weeks of age. Data represent the mean ± SEM (∗p < 0.0001).(F) Pharmacokinetic analysis of JQ1 in plasma (black lines) and testis (red lines) following twice-daily (BID) administration of JQ1 (50 mg/kg IP) to male mice. Data represent the mean ± SD.(G) Testis weights (mg) from mice treated with control or JQ1 (50 mg/kg BID) from 9–12 weeks of age. Data represent the mean ± SEM (∗p < 0.05).(H) Sperm counts obtained from the cauda epididymis of males treated from 9–12 weeks of age with vehicle or JQ1 (50 mg/kg BID). Data represent the mean ± SEM (∗p < 0.05).(I) Motility of mature sperm obtained from the cauda epididymis of adult males treated with JQ1 (50 mg/kg BID) or vehicle from 9–12 weeks. Data represent the mean ± SEM (∗p < 0.001).(J) Cross-sectional area of seminiferous tubules from JQ1-treated mice (50 mg/kg QD for 3–6 weeks or 6–12 weeks, or 50 mg/kg BID for 9–12 weeks, as shown) or control (∗p < 0.05).(K, L, and M) Male mice treated with JQ1 or vehicle from 6–12 weeks exhibit statistically similar serum levels of (K) testosterone, (L) luteinizing hormone (LH), and (M) follicle-stimulating hormone (FSH).See also Figure S1 and Tables S3 and S4.
Mentions: To test the ability of JQ1 to reach its contraceptive target cells, the testicular bioavailability of JQ1 was assessed by serum and tissue pharmacokinetic analysis. Following a single intraperitoneal (i.p.) dose of JQ1 (50 mg/kg) in male mice, measurements of JQ1 concentration were made in serum, testis, and brain (Figure 3A and Table S3). Overall, JQ1 exhibits excellent testicular bioavailability (AUCtestis/AUCplasma = 259%), suggesting preferential distribution into this tissue compartment with rapid (Tmax = 0.25 hr) and pronounced exposure (Cmax = 34 μg/ml). Corroborating barrier permeability by JQ1, nearly uniform blood-brain barrier permeability was observed after single-dose pharmacokinetic studies (AUCbrain/AUCplasma = 98%).

Bottom Line: 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.Biochemical and crystallographic studies confirm that occupancy of the BRDT acetyl-lysine binding pocket by JQ1 prevents recognition of acetylated histone H4.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA. mmatzuk@bcm.edu

Show MeSH
Related in: MedlinePlus