Small-Molecule Inhibition of BRDT for Male Contraception

Matzuk, Martin M.; McKeown, M.; Filippakopoulos, P.; Li, Qinglei; Ma, Lang; Agno, Julio E.; Lemieux, Madeleine E.; Picaud, S.; Yu, Richard N.; Qi, Jun; Knapp, Stefan; Bradner, James E.

doi:10.1016/j.cell.2012.06.045

Cited by 365 publications

(382 citation statements)

References 50 publications

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“…In the present study, we confirmed that intraperitoneal injection of JQ1 did not exert any adverse effect especially on normal bone [15,32]. A moderate increased bone mass was observed without affecting any bone strength parameters.…”

supporting

confidence: 86%

Inhibition of BET proteins and epigenetic signaling as a potential treatment for osteoporosis

Baud’huin

Lamoureux

Jacques

et al. 2017

Bone

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Histone modifications are important for maintaining the transcription program. BET proteins, an important class of "histone reading proteins", have recently been described as essential in bone biology. This study presents the therapeutic opportunity of BET protein inhibition in osteoporosis. We find that the pharmacological BET protein inhibitor JQ1 rescues pathologic bone loss in a post-ovariectomy osteoporosis model by increasing the trabecular bone volume and restoring mechanical properties. The BET protein inhibition suppresses osteoclast differentiation and activity as well as the osteoblastogenesis in vitro. Moreover, we show that treated non-resorbing osteoclasts could still activate osteoblast differentiation. In addition, specific inhibition of BRD4 using RNA interference inhibits osteoclast differentiation but strongly activates osteoblast mineralization activity. Mechanistically, JQ1 inhibits expression of the master osteoclast transcription factor NFATc1 and the transcription factor of osteoblast Runx2. These findings strongly support that targeting epigenetic chromatin regulators such as BET proteins may offer a promising alternative for the treatment of bone-related disorders such as osteoporosis.

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supporting

confidence: 86%

Inhibition of BET proteins and epigenetic signaling as a potential treatment for osteoporosis

Baud’huin

Lamoureux

Jacques

et al. 2017

Bone

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“…Although the pharmacologic properties of JQ1 are not ideal for in vivo studies (Matzuk et al 2012), we tested its activity against IDH2 mutant AML in vivo. Mice were transplanted with IDH2 R172K AML and, upon engraftment, treated (day 5) with vehicle or 50 mg/kg per day JQ1 by gavage for 2 wk (Filippakopoulos et al 2010;Zuber et al 2011b).…”

Section: Idh Mutant Amls Rapidly Differentiate In Response To Brd4 Inmentioning

confidence: 99%

Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition

et al. 2013

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Somatic mutations in the isocitrate dehydrogenase (IDH) genes IDH1 and IDH2 occur frequently in acute myeloid leukemia (AML) and other cancers. These genes encode neomorphic proteins that produce the presumed oncometabolite 2-hydroxyglutarate (2-HG). Despite the prospect of treating AML and other cancers by targeting IDH mutant proteins, it remains unclear how these mutants affect tumor development and maintenance in vivo, and no cancer models exist to study the action of IDH2 mutants in vivo. We show that IDH2 mutants can cooperate with oncogenic Flt3 or Nras alleles to drive leukemia in mice by impairing the differentiation of cells of the myeloid lineage. Pharmacologic or genetic inhibition of IDH2 triggers the differentiation and death of AML cells, albeit only with prolonged IDH2 inhibition. In contrast, inhibition of the bromodomain-containing protein Brd4 triggers rapid differentiation and death of IDH2 mutant AML. Our results establish a critical role for mutant IDH2 in leukemogenesis and tumor maintenance and identify an IDH-independent strategy to target these cancers therapeutically.

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“…Matzuk et al [6] discovered one such contraceptive target, the testis-specific and bromodomain-containing protein BRDT, and provided pharmacological validation of it as a target for male contraception. In our study, sAC was considered to be a potential contraceptive target, because it is located in the nucleus, mitochondria and microtubules [8], it is expressed in mammalian spermatozoa [9] and it is highly enriched in male germ cells [10].…”

Section: Discussionmentioning

confidence: 99%

“…To develop non-hormonal male contraceptives, developing small molecules that could target spermatogenesis-specific proteins that are essential for both sperm production and fertility in mammals appears attractive [5]. A selective small-molecule inhibitor (JQ1) of the testis-specific and bromodomain-containing protein BRDT is a good contraceptive agent targeting the male germ cells for contraception [6]. A short hairpin (sh)RNA aimed at silencing the expression of CatSper2, the key protein involved in rat sperm hyperactivation, is also considered to be a target for male contraception [7].…”

mentioning

confidence: 99%

Knockdown of sAC affects sperm hyperactivation by cAMP-signaling pathway in male rat (Rattus norvegicus)

Zhou

Jiang

et al. 2013

Chin. Sci. Bull.

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Soluble adenylyl cyclase (sAC) plays a critical role in male fertility in mammals by regulating sperm hyperactivation. We aimed to study the mechanism of sAC in this phenomenon and to explore potential target sites for male contraception. In this study, in vivo electroporation and rete testis microinjection-mediated short hairpin (sh)RNA plasmids were adopted to silence sAC gene expression in male rats. The results showed that high transfection efficiency (shRNA717, 49.0% and shRNA4205, 65.0%) was achieved by shRNA plasmids injected directly into the rete testis. When the sAC was downregulated, the cyclic adenosine monophosphate (cAMP) content and protein phosphorylation level of spermatozoa both declined with a significantly lower hyperactivation rate compared with negative controls. The highest transfection efficiency occurred at 15 d and was obviously time dependent. Bioinformatic and experimental results showed that sAC and tmAC both belong to the AC family and might have analogous functions. ShRNA717 and shRNA4205 were the best targets for the sAC gene, suggesting that they could be candidates for male contraception. Thus, it appears feasible to achieve male contraception by silencing the expression of sAC, affecting sperm hyperactivation via a cAMP-mediated signaling pathway.Rattus norvegicus, sAC, male contraception, hyperactivation, cAMP, shRNA Citation:Yu J, Zhou S, Jiang X Q, et al. Knockdown of sAC affects sperm hyperactivation by cAMP-signaling pathway in male rat (Rattus norvegicus). Chin Sci Bull, 2013, 58: 32563265,

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Small-Molecule Inhibition of BRDT for Male Contraception

Cited by 365 publications

References 50 publications

Inhibition of BET proteins and epigenetic signaling as a potential treatment for osteoporosis

Inhibition of BET proteins and epigenetic signaling as a potential treatment for osteoporosis

Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition

Knockdown of sAC affects sperm hyperactivation by cAMP-signaling pathway in male rat (Rattus norvegicus)

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