Brdttndm gst bromodomain testisspecific protein ct9. As previously discussed, brdt is a testisspecific gene that when individually ablated in mice results in arrest of male meiosis, azoospermia, and complete male infertility barda et al. Bromodomain protein brd4 is a transcriptional repressor of autophagy and lysosomalfunction. Sep 07, 2012 these findings are complimented by a recent publication in cell matzuk et al, 2012 where jq1, a small molecule bet inhibitor, is effective as a male contraceptive in mice. Research indicates that 5071% of men would be interested in using a reversible contraceptive method. Design and synthesis of brdt selective inhibitors as male contraceptive agents part 2. While women have multiple reversible contraceptive options, there is an unmet need for men to pursue safe and reversible infertility. The bromodomain and extraterminal bet family proteins, consisting of brd2, brd3, brd4, and testisspecific brdt members, are epigenetic readers and play a key role in the regulation of gene transcription. Swissdock, a protein small molecule docking web service based. Combined with coimmunoprecipitation assay, we demonstrated that brd4 might interact with ampk. Jq1 blocks the production of sperm in the testes by inhibiting brdt, however.
It was developed by the james bradner laboratory at brigham and womens hospital and named after chemist jun qi. Recently, several synthesized smallmolecule chemical compounds targeting bet proteins. Oct 16, 2019 individuals with mutations in the brdt gene have infertility from abnormal formation of sperm heads. Bromodomain protein brd4 is a transcriptional repressor of autophagy and. Structural studies of brdt 1 bound to jq1 reveal ligandreceptor shape complementarity and complete occlusion of the acetyllysine recognition cavity. Here, we report potent inhibition of the testisspecific member brdt, which is essential for chromatin remodeling during spermatogenesis. These include methods like risugvasalgel which has completed a small phase ii. Improvements in safety, user convenience, acceptability, and availability of products remain important goals of the. Brdt is a testisspecific contraceptive target, and jq1 is a brdt inhibitor that causes a reversible contraceptive effect in male mice.
The profound and broad pharmacology of bromodomain inhibition, especially that associated with the bet family of bromodomains brd2, brd3, brd4 and brdt, has led to the progression of a number of small molecule assets into the clinic. We have shown that jq1, a selective smallmolecule inhibitor of the bet subfamily, induces a complete and reversible contraceptive effect in mice 4. Mar 02, 2021 deletions of either bd1 or both bd1 and bd2 in the mouse brdt gene result in male sterility 2, 3, indicating that brdt is a testisspecific target for male contraception. Brdt is a contraceptive target jq1 is a brdt inhibitor that causes a reversible contraceptive effect in male mice jq1 alters spermatogenesis at the spermatocyte and round spermatid. Jq1 is not the pill for men, because it also binds other members of the bromodomain family, he said. Pdf smallmolecule inhibition of brdt for male contraception. Mckeown,7 panagis filippakopoulos,8 qinglei li,9 lang. Aug 24, 2012 brdt is activated at the onset of meiosis. Thus, a small molecule that specifically inhibits brdt function represents a suitable choice for a male contraceptive. The human bet family brd2, brd3, brd4 and brdt which all contain two conserved bromodomains per target, plays a key role regulating transcription of growth. Spring 2020 systems biology of reproduction lecture outline. We have shown that jq1, a selective smallmolecule inhibitor of the bet subfamily, induces a complete and reversible contraceptive effect in. Male contraceptives, also known as male birth control, are methods of preventing pregnancy.
Focused library synthesis for tgr5 takeda g proteincoupled receptor 5 antagonist jiang, jiewei 2020 view download file. The first bromodomain of the testisspecific double bromodomain protein brdt is required for chromocenter organization that is modulated by genetic background. N, ndimethylacetamide dma, an fda approved solvent, acts as a low affinity inhibitor for brd2 and brd4 ghayor et al. The chemical structure was inspired by patent of similar bet inhibitors.
Dec 07, 2017 upon the basis of the cancer genome atlas tcga data set, we identified that several autophagyrelated proteins such as ampactivated protein kinase ampk were remarkably downregulated in breast cancer. One approach to reducing unintended pregnancies is the use of effective contraceptive methods. The rpkm value of all genes in these 6 samples has been deposited in an excel file in suppleme. Smallmolecule inhibition of brdt for male contraception by martin m. Design and synthesis of brdt selective inhibitors as. The histograms represent the values of biological duplicates normalized with respect to actin as a control gene and to brdt mean expression in 50. Bet inhibitor jq1 is a potential lead compound for male contraceptives in view of the important role of brdt in spermatogenesis, brdt will soon become a star target in the development of male contraceptives. A pharmacologic approach to male contraception remains a longstanding challenge in medicine. This arrangement creates a deep largely hydrophobic acetyl lysine binding cavity which constitutes an attractive pocket for the development of selective protein interaction inhibitors. It was developed by the james bradner laboratory at brigham and womens hospital. Notably, inhibitors that block protein interactions have been identified for chromatinbinding proteins and apoptosis proteins such as p53 and bcl2. In addition, a small molecule, jq1, blocks the binding of brdt to acetylated histone, resulting in reversible contraceptive effects in mice.
Mckeown,7 panagis filippakopoulos,8 qinglei li,9 lang ma,1 julio e. Research advanced in small molecular inhibitors of human brdt. In contrast, nonhormonal male contraceptive lead compounds target sertoli cells and. Transcriptional activation requires the bromodomain reading function of brd4, which recognizes acetylation marks aclabeled cyan triangles on histone. Bet bromodomain inhibition as a therapeutic strategy to target cmyc. Small molecule may provide direction in quest for male. Frontiers reversible contraceptive potential of fda. These data establish a rationale for the development of a new contraceptive that can cross the bloodtestis boundary and inhibit bromodomain activity during spermatogenesis, providing a lead compound targeting the male germ cell for contraception matzuk et al. Mar 03, 2012 small molecule bet inhibitors like jq1 bind to the bromodomains of brdt, preventing it from binding to acetylated histones and performing its dual role during spermatogenesis. Jan 01, 2019 validation of brdt as a nonhormonal male contraceptive target was further strengthened by pharmacological inhibition of brdt. Consisting of two parts with twelve chapters, it demonstrates the design strategies and case studies of small molecule ppi inhibitors. As brdt is expressed only in mid to laterterm spermatocytes and not in mitotically dividing spermatogonia, a brdt specific inhibitor would not affect the spermatogonial stem cell population, making any small molecule brdt inhibition reversible and leading to no ill effects on subsequent mature spermatids.
Therefore, identifying a small molecule inhibitor against an individually dispensable target would yield no contraceptive effect. Male contraceptives, also known as male birth control, are methods of preventing pregnancy that solely involve the male physiology. Research advanced in small molecular inhibitors of human. Aug 17, 2012 bromodomain, testisspecific brdt is a contraceptive target jq1 is a brdt inhibitor that causes a reversible contraceptive effect in male mice jq1 alters spermatogenesis at the spermatocyte and round spermatid stages jq1 treatment targets the male germline and reduces spermatozoa number and motility. Discovery of a smallmolecule bromodomaincontaining. The development of a male contraceptive pill has long proven to be elusive, but findings from a new. Bet proteins brd2, brd3, brd4 and the testis specific brdt have a conserved modular. Development of novel male contraceptives amory 2020. Core set using the bifc stable cell line in the 384well format. Clinical progress and pharmacology of small molecule. Such files may be downloaded by article for research use if there is a. The high similarity between bromodomain proteins of the bet family makes development of selective and specific inhibitors both difficult and necessary.
Pipeline for contraceptive development fertility and sterility. Hormonal methods of contraception using testosterone have shown good results. Sep 17, 20 classes of small molecule inhibitors1,2 of brds have been reported. The most common kinds of male contraception include condoms, outercourse, and vasectomy. In domestic animals, castration is commonly used for contraception. Numerous smallmolecule compounds with potent inhibitory activity against bet family proteins have been reported. After analyses of the pharmacophore and wpf interaction optimization, we designed a small. Small molecule inhibition of brdt for male contraception. Jq1 is a thienotriazolodiazepine and a potent inhibitor of the bet family of bromodomain proteins which include brd2, brd3, brd4, and the testisspecific protein brdt in mammals. These molecules are visualized, downloaded, and analyzed by users who range from students to specialized scientists.
Wholeexome sequencing identified a homozygous brdt mutation. A pharmacologic approach to male contraception remains a. Jun 27, 2018 knockout studies in mice have validated brdt 1 as a potential target for male nonhormonal contraception, and the panbet inhibitor jq1 was identified as an effective and reversible contraceptive. Toward this objective, we explored the spermatogenic effects of a selective small molecule inhibitor jq1 of the bromodomain and. Users can perform simple and advanced searches based on annotations relating to sequence, structure and function. Progress in developing new reversible male contraception has been slow. The most important reason is the conservative sequence between brdt and other members of bet protein family, which leads to the lack of speciesspecific inhibitors to brdt. Cancer, oncology, neuroblastoma, bet inhibitors, p53, pediatric, mycn amplifications, jq1. While the hormonal approach has been clearly shown to be capable of providing effective and reversible contraception, there remains no product available. Bet bromodomain inhibitors with onestep synthesis discovered. Targeting myc dependence in cancer by inhibiting bet bromodomains.
Pipeline for contraceptive development fertility and. Non hormonal reversible methods of male contraception like reversible inhibition of sperm under guidanceare very. Discovery of a smallmolecule degrader of bromodomain and. One of the most advanced bet bromodomain inhibitors is 1 ibet762 or gsk525762, figure 2, which was recently advanced into a phase i clinical trial for treatment of human nuclear protein in testis nut midline carcinoma, a rare but. Unintended pregnancies can have significant adverse socioeconomic effects and health risks for women.
The rcsb pdb also provides a variety of tools and resources. Model for jq1 smallmolecule inhibition of the brd4 bromodomain in cancer. The control of male fertility by spermatidspecific. Mckeown, panagis filippakopoulos, qinglei li, lang ma, julio e. Although female contraceptives are very effective at preventing unintended pregnancy, some women can not use them because of health conditions or sideeffects, leaving some couples without effective contraceptive options. As a member of the wwpdb, the rcsb pdb curates and annotates pdb data according to agreed upon standards.
Selective inhibition of brdt by a small molecule is an exciting new target in the search for a new nonhormonal male contraceptive. Currently, trials of a selfadministered gel combination of testosterone and the progestogen nestorone are under way, complementing the largely injectable methods. The high rates of unplanned pregnancy reflect an unmet need for effective contraceptive methods for women, especially for individuals with health risks such as obesity, diabetes, hypertension, and other conditions that may contraindicate use of an estrogencontaining product. Furthermore, brdt is not expressed in mitotically dividing spermatogonia, and thus a brdt specific inhibitor would not affect the spermatogonial stem cell population, theoretically making any spermatogenic impairment reversible.
The development for a hormonal male contraceptive has been hampered by. Metabolism of jq1, an inhibitor of bromodomain and extra. Pdf bromodomaindependent stagespecific male genome. Knockout studies in mice have validated brdt 1 as a potential target for male nonhormonal contraception, and the panbet inhibitor jq1 was identified as an effective and reversible contraceptive. A the aberrant transcriptional activation of myc target genes indicated as red shaded regions of chromatin is a common feature of many cancers. The small molecule inhibitor ep055, which targets eppin, causes. The rpkm value of all genes in these 6 samples has been deposited in an excel file in supplementary table 4. To screen for potential small molecule inhibitors of the. Jq1 treatment produces a reversible contraceptive effect by targeting the activity of brdt in mouse male germ cells, validating brdt as a male contraceptive target. The making of i bet762, a bet bromodomain inhibitor now in.
Here, we report potent inhibition of the testisspecific member brdt, which is essential for chromatin. Smallmolecule inhibition of brdt for male contraception martin m. Mckeown, with 357 highly influential citations and 9 scientific research papers. Other forms of male contraception are in various stages of research and development. It is time for new male contraceptives declaration of the international consortium for male contraception icmc on may 4, 2016, at the first icmc congress in paris, at the french national academy of medicine. Recently, heterobifunctional smallmolecule bet degraders have been designed. Condoms dominate as the most widely used form of male contraception as they provide a somewhat high contraceptive success rate 98% with perfect use but only 83% with actual use. Nov 10, 2020 it was shown that inhibition of brdt by small bet inhibitor jq1 leads to reversible contraception in male mice matzuk et al. Male contraceptive initiatives mci mission is to facilitate research and development of male contraceptives for people around the world and to build awareness among researchers, donors and the general public about the demand for and status of novel male contraceptive methods. Identification of novel potent human testisspecific and. Recent progress in the discovery of nonhormonal male contraceptive agents houkjung organic colloquium. This is a pdf file of an unedited manuscript that has been accepted for. One study showed that jq1, a small molecule inhibitor of brdt, was able to cross the bloodtestis barrier and cause complete, reversible contraceptive activity in male mice 45. Thus, there is a great need for male contraceptives to prevent unintended pregnancies, of which.
Brdt inhibitors for male contraceptive drug discovery. Jq1 is a smallmolecule inhibitor of the bromodomain and extra terminal bet protein family that potently inhibits the bromodomain testisspecific protein brdt, which is essential for spermatogenesis. Mar 01, 20 recent and parallel studies of spermatogenesis, either under general inhibition of bet bomodomains by bet inhibitor jq1 6 or in the context of mouse genetic mutants for brdt, the testisspecific bet member, provided insight into the functions of the different bet members and, in the case of brdt, into how the two bromodomains are involved in. Results molecular recognition of brdt by jq1 to assess competitive binding to brdt 1, we devised homogeneous, luminescence proximity assays that are capable of quantifying binding of a synthetic, biotinylated tetraacetylated. Jq1, a selective brdt inhibitor which acts in this manner, is currently under development as a nonhormonal male contraceptive drug. A recent study in cell used the small molecule bet inhibitor jq1 to disrupt spermatogenesis in mice matzuk, 2012.
Given the largely untapped vast pharmacological space. Spermspecific calcineurin contains a catalytic subunit. Matzuk et al smallmolecule inhibition of brdt for male contraception. Toward this objective, we explored the spermatogenic effects of a selective smallmolecule inhibitor jq1 of the bromodomain and extraterminal bet subfamily of epigenetic reader proteins. A study showed that jq1, a smallmolecule inhibitor of brdt, was able to cross the bloodtestis barrier and cause complete, reversible contraceptive activity in male mice. In addition, a small molecule, jq1, blocks the binding of brdt to acetylated. Discovery and characterization of bromodomain 2specific. Inhibition of chromatin remodeling by binding to a pocket on brdt has been shown to produce reversible sterility in male mice. Jq1, a selective brdt inhibitor which acts in this manner, is currently under. At present, effective male contraceptive options are condoms and vasectomy. Potential novel male contraceptives can be divided into those based.
Smallmolecule inhibition of brdt for male contraception free download as pdf file. Smallmolecule inhibition of brdt for male contraception core. The expression of brdt brdt was analysed either by rtqpcr a or by western blots b. Targeting proteinprotein interactions by small molecules.
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. In addition, many men wish to take active responsibility for family planning. Currently there are several contraceptive options available to men, however. Galactosidase activity, driven by brdt gene promoter, was assessed in seminiferous. Both studies establish brdt as an integral factor in sperm development. The research points to a new direction in research in male contraceptives, said matzuk. We report here that direct inhibition of brdt by a smallmolecule bromodomain inhibitor exerts a dose and timedependent inhibitory effect on spermatogenesis. The data was obtained from a tabseparated file including ensembl gene. Bet proteins are considered to be attractive therapeutic targets for cancer and other human diseases. When are the bet factors the most sensitive to bromodomain. Bromodomain and extraterminal domain inhibitors beti for. Discovery of a smallmolecule bromodomaincontaining protein. Smallmolecule inhibition of brdt for male contraception. Aug 01, 2012 bromodomain, testisspecific brdt is a contraceptive target jq1 is a brdt inhibitor that causes a reversible contraceptive effect in male mice jq1 alters spermatogenesis at the spermatocyte and round spermatid stages jq1 treatment targets the male germline and reduces spermatozoa number and motility.
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