气候变化领域集成服务门户(CCPortal): Discovery and characterization of bromodomain 2-specific inhibitors of BRDT

CCPortal

DOI	10.1073/pnas.2021102118
	Discovery and characterization of bromodomain 2-specific inhibitors of BRDT
	Yu Z.; Ku A.F.; Anglin J.L.; Sharma R.; Ucisik M.N.; Faver J.C.; Li F.; Nyshadham P.; Simmons N.; Sharma K.L.; Nagarajan S.; Riehle K.; Kaur G.; Sankaran B.; Storl-Desmond M.; Palmer S.S.; Young D.W.; Kim C.; Matzuk M.M.
发表日期	2021
ISSN	00278424
卷号	118 期号:9
英文摘要	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 BRDTBD2. 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. © This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
英文关键词	BET bromodomains; DNA-encoded chemistry; Male contraceptive; Small-molecule inhibitors
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180441
作者单位	Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, United States; Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX 77030, United States; Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, United States; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, United States
推荐引用方式 GB/T 7714	Yu Z.,Ku A.F.,Anglin J.L.,et al. Discovery and characterization of bromodomain 2-specific inhibitors of BRDT[J],2021,118(9).
APA	Yu Z..,Ku A.F..,Anglin J.L..,Sharma R..,Ucisik M.N..,...&Matzuk M.M..(2021).Discovery and characterization of bromodomain 2-specific inhibitors of BRDT.Proceedings of the National Academy of Sciences of the United States of America,118(9).
MLA	Yu Z.,et al."Discovery and characterization of bromodomain 2-specific inhibitors of BRDT".Proceedings of the National Academy of Sciences of the United States of America 118.9(2021).