ArticleProceedings of the National Academy of Sciences of the United States of America2021
Discovery and characterization of bromodomain 2-specific inhibitors of BRDT.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 65 citations in OpenAlex.
- WFS1 Deficiency Impairs PIAS4-Associated SUMOylation and Increases Ubiquitin-Mediated Spermatogenesis-Related Protein Degradation Leading to Testicular Male Infertility.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Identification of potent inhibitors of JUN N-terminal kinases for treatment of endometriosis and associated pain.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Targeting bromodomain and extraterminal proteins in cardiovascular disease: Pathological mechanisms and therapeutic applications.The Journal of international medical research · 2026Review
- Molecular interplay between sperm and oocyte: a narrative review.Human reproduction update · 2026Review
- Structural Basis for BD1-Preferring 2,4-Disubstituted Pyrimidine BRDT Inhibitors.Journal of medicinal chemistry · 2026Article
- Universal Baseline forbioRxiv : the preprint server for biology · 2026Article
- Epigenetic Dysregulation in Cancer: Implications for Gene Expression and DNA Repair-Associated Pathways.International journal of molecular sciences · 2025Review
- Macrocyclic dihydropyridine analogs as pan-BET BD2-preferred inhibitors.European journal of medicinal chemistry · 2025Article
- Identifying a non-conserved site for achieving allosteric covalent inhibition of CECR2.Acta pharmacologica Sinica · 2025Article
- Discovery of highly potent and ALK2/ALK1 selective kinase inhibitors using DNA-encoded chemistry technology.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Chem-CRISPR/dCas9FCPF: a platform for chemically induced epigenome editing.Nucleic acids research · 2024Article
- Novel Genes of the Male Reproductive System: Potential Roles in Male Reproduction and as Non-hormonal Male Contraceptive Targets.Molecular reproduction and development · 2024Review
- Advances in Male Contraception: When Will the Novel Male Contraception be Available?The world journal of men's health · 2024Review
- Building Block-Centric Approach to DNA-Encoded Library Design.Journal of chemical information and modeling · 2024Article
- Identification of potent pan-ephrin receptor kinase inhibitors using DNA-encoded chemistry technology.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Male contraception: narrative review of ongoing research.Basic and clinical andrology · 2023Review
- Article
- Small-molecule discovery through DNA-encoded libraries.Nature reviews. Drug discovery · 2023Review
- DNA-encoded chemical libraries yield non-covalent and non-peptidic SARS-CoV-2 main protease inhibitors.Communications chemistry · 2023Article
- Non-Hormonal Contraception.Journal of clinical medicine · 2023Review
Corrections and comments
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Authors and funding
19 authors at 2 institutions in 1 country.
Funding
Abstract
Bromodomain testis (BRDT), a member of the bromodomain and extraterminal (BET) subfamily that includes the cancer targets BRD2, BRD3, and BRD4, is a validated contraceptive target. All BET subfamily members have two tandem bromodomains (BD1 and BD2). Knockout mice lacking BRDT-BD1 or both bromodomains are infertile. Treatment of mice with JQ1, a BET BD1/BD2 nonselective inhibitor with the highest affinity for BRD4, disrupts spermatogenesis and reduces sperm number and motility. To assess the contribution of each BRDT bromodomain, we screened our collection of DNA-encoded chemical libraries for BRDT-BD1 and BRDT-BD2 binders. High-enrichment hits were identified and resynthesized off-DNA and examined for their ability to compete with JQ1 in BRDT and BRD4 bromodomain AlphaScreen assays. These studies identified CDD-1102 as a selective BRDT-BD2 inhibitor with low nanomolar potency and >1,000-fold selectivity over BRDT-BD1. Structure-activity relationship studies of CDD-1102 produced a series of additional BRDT-BD2/BRD4-BD2 selective inhibitors, including CDD-1302, a truncated analog of CDD-1102 with similar activity, and CDD-1349, an analog with sixfold selectivity for BRDT-BD2 versus BRD4-BD2. BROMOscan bromodomain profiling confirmed the great affinity and selectivity of CDD-1102 and CDD-1302 on all BET BD2 versus BD1 with the highest affinity for BRDT-BD2. Cocrystals of BRDT-BD2 with CDD-1102 and CDD-1302 were determined at 2.27 and 1.90 Å resolution, respectively, and revealed BRDT-BD2 specific contacts that explain the high affinity and selectivity of these compounds. These BD2-specific compounds and their binding to BRDT-BD2 are unique compared with recent reports and enable further evaluation of their nonhormonal contraceptive potential in vitro and in vivo.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.