BRDT Inhibitors for Male Contraceptive Drug Discovery: Current Status

Miao, Zhenyuan; Guan, Xianghong; Jiang, Jiewei; Georg, Gunda I.

doi:10.1007/978-981-13-0773-7_11

Cited by 4 publications

(4 citation statements)

References 76 publications

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“…Brdt is only expressed in the testes, and it is a validated male contraceptive drug target [ 95 , 96 ]. Brdt has attracted attention for the design of novel non-hormonal male contraceptives [ 93 , 97 ]. On the other hand, Brd4 is ubiquitously expressed, and it is a promising anticancer target.…”

Section: Evolution Of Small-molecule Inhibitors Of Bet Proteinsmentioning

confidence: 99%

BET Bromodomain Inhibitors: Novel Design Strategies and Therapeutic Applications

Xing

Larue

et al. 2023

Molecules

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The mammalian bromodomain and extra-terminal domain (BET) family of proteins consists of four conserved members (Brd2, Brd3, Brd4, and Brdt) that regulate numerous cancer-related and immunity-associated genes. They are epigenetic readers of histone acetylation with broad specificity. BET proteins are linked to cancer progression due to their interaction with numerous cellular proteins including chromatin-modifying factors, transcription factors, and histone modification enzymes. The spectacular growth in the clinical development of small-molecule BET inhibitors underscores the interest and importance of this protein family as an anticancer target. Current approaches targeting BET proteins for cancer therapy rely on acetylation mimics to block the bromodomains from binding chromatin. However, bromodomain-targeted agents are suffering from dose-limiting toxicities because of their effects on other bromodomain-containing proteins. In this review, we provided an updated summary about the evolution of small-molecule BET inhibitors. The design of bivalent BET inhibitors, kinase and BET dual inhibitors, BET protein proteolysis-targeting chimeras (PROTACs), and Brd4-selective inhibitors are discussed. The novel strategy of targeting the unique C-terminal extra-terminal (ET) domain of BET proteins and its therapeutic significance will also be highlighted. Apart from single agent treatment alone, BET inhibitors have also been combined with other chemotherapeutic modalities for cancer treatment demonstrating favorable clinical outcomes. The investigation of specific biomarkers for predicting the efficacy and resistance of BET inhibitors is needed to fully realize their therapeutic potential in the clinical setting.

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Section: Evolution Of Small-molecule Inhibitors Of Bet Proteinsmentioning

confidence: 99%

BET Bromodomain Inhibitors: Novel Design Strategies and Therapeutic Applications

Xing

Larue

et al. 2023

Molecules

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“…BRDT is a validated male contraceptive target , and the subject of drug development efforts toward nonhormonal male contraceptives. , BRDT has two distinct functions during spermatogenesis, initiation of meiotic gene expression, and postmitotic removal of histones from the nucleosome to facilitate the compaction of genes into the sperm head. , BRDT has also been identified as a potential cancer target in a subset of esophageal squamous cell carcinomas …”

Section: Introductionmentioning

confidence: 99%

Bivalent BET Bromodomain Inhibitors Confer Increased Potency and Selectivity for BRDT via Protein Conformational Plasticity

et al. 2022

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Bromodomain and extraterminal domain (BET) proteins are important regulators of gene transcription and chromatin remodeling. BET family members BRD4 and BRDT are validated targets for cancer and male contraceptive drug development, respectively. Due to the high structural similarity of the acetyl-lysine binding sites, most reported inhibitors lack intra-BET selectivity. We surmised that protein–protein interactions induced by bivalent inhibitors may differ between BRD4 and BRDT, conferring an altered selectivity profile. Starting from nonselective monovalent inhibitors, we developed cell-active bivalent BET inhibitors with increased activity and selectivity for BRDT. X-ray crystallographic and solution studies revealed unique structural states of BRDT and BRD4 upon interaction with bivalent inhibitors. Varying spacer lengths and symmetric vs unsymmetric connections resulted in the same dimeric states, whereas different chemotypes induced different dimers. The findings indicate that the increased intra-BET selectivity of bivalent inhibitors is due to the differential plasticity of BET bromodomains upon inhibitor-induced dimerization.

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“…4 Mutagenesis studies have shown that loss of BRDT-BD1 (BRDT-1) results in abnormal spermatids and complete sterility in mice 5 making BRDT-1 an attractive target for developing nonhormonal male contraceptives. 6 The greatest challenge for BRD drug discovery efforts is identifying compounds that are selective for individual BRD proteins due to the high homology of KAc binding sites within BRD families. 7 In addition, the discovery of potent inhibitors with high selectivity for BD1 over BD2 (or BD2 over BD1) has been challenging because, although the BET BRD loop regions are variable, the BD1 and BD2 substrate binding pockets show high sequence similarity.…”

mentioning

confidence: 99%

“…While BRD2, 3, and 4 are ubiquitously expressed, BRDT is exclusively found in the testis . Mutagenesis studies have shown that loss of BRDT-BD1 (BRDT-1) results in abnormal spermatids and complete sterility in mice making BRDT-1 an attractive target for developing nonhormonal male contraceptives . The greatest challenge for BRD drug discovery efforts is identifying compounds that are selective for individual BRD proteins due to the high homology of KAc binding sites within BRD families .…”

mentioning

confidence: 99%

Design, Synthesis, and Characterization of a Fluorescence Polarization Pan-BET Bromodomain Probe

Kingsley

Guan

Ayoub

et al. 2018

ACS Med. Chem. Lett.

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Several chemical probes have been developed for use in fluorescence polarization screening assays to aid in drug discovery for the bromodomain and extra-terminal domain (BET) proteins. However, few of those have been characterized in the literature. We have designed, synthesized, and thoroughly characterized a novel fluorescence polarization pan-BET chemical probe suitable for high-throughput screening, structure−activity relationships, and hit-to-lead potency and selectivity assays to identify and characterize BET bromodomain inhibitors.

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BRDT Inhibitors for Male Contraceptive Drug Discovery: Current Status

Cited by 4 publications

References 76 publications

BET Bromodomain Inhibitors: Novel Design Strategies and Therapeutic Applications

BET Bromodomain Inhibitors: Novel Design Strategies and Therapeutic Applications

Bivalent BET Bromodomain Inhibitors Confer Increased Potency and Selectivity for BRDT via Protein Conformational Plasticity

Design, Synthesis, and Characterization of a Fluorescence Polarization Pan-BET Bromodomain Probe

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