BET Bromodomain Inhibitors: Novel Design Strategies and Therapeutic Applications

Molecules, Journal Year: 2023, Volume and Issue: 28(7), P. 3043 - 3043

Published: March 29, 2023

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

Language: Английский

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Systemic and Local Strategies for Primary Prevention of Breast Cancer

Cancers, Journal Year: 2024, Volume and Issue: 16(2), P. 248 - 248

Published: Jan. 5, 2024

One in eight women will develop breast cancer the US. For with moderate (15–20%) to average (12.5%) risk of cancer, there are few options available for reduction. high-risk (>20%) women, such as BRCA mutation carriers, primary prevention strategies limited evidence-based surgical removal breasts and/or ovaries and anti-estrogen treatment. Despite their effectiveness reduction, not many individuals opt or hormonal interventions due severe side effects potentially life-changing outcomes key deterrents. Thus, better communication about benefits existing development new minimal needed offer adequate risk-reducing interventions. We extensively review discuss innovative investigational prevention. Most these at pre-clinical stage, but some already being evaluated clinical trials others expected lead first-in-human within 5 years. Likely, would be initially tested may applicable lower-risk if shown decrease a similar rate strategies, effects.

Language: Английский

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Targeting epigenetic regulation for cancer therapy using small molecule inhibitors

Advances in cancer research, Journal Year: 2023, Volume and Issue: unknown, P. 73 - 161

Published: Jan. 1, 2023

Language: Английский

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Epigenetic Alterations That Are the Backbone of Immune Evasion in T-cell Malignancies

Cureus, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 4, 2024

Epigenetic alterations are heritable and enduring modifications in gene expression that play a pivotal role immune evasion. These include to noncoding RNA, DNA methylation, histone modifications. methylation plays crucial normal cell growth development but patterns such as hypermethylation or hypomethylation can enable tumor viral cells evade host responses. Histone also inhibit responses by promoting the of genes involved suppressing function. In case T-cell lymphoma, adult lymphomas (ATL) undergo evasion through exceptional function its accessory regulatory genes. therapies emerging promising adjunct traditional immunotherapy chemotherapy regimens. Clinical trials currently investigating use epigenetic combination with immunotherapies chemotherapies for more effective treatment ATL other cancers. This review highlights widely found malignancies.

Language: Английский

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Targeted therapy for rare lung cancers: Status, challenges, and prospects

Molecular Therapy, Journal Year: 2023, Volume and Issue: 31(7), P. 1960 - 1978

Published: May 13, 2023

Lung cancer causes the most cancer-related deaths worldwide. In recent years, molecular and immunohistochemical techniques have rapidly developed, further inaugurating an era of personalized medicine for lung cancer. The rare subset cancers accounts approximately 10%, each displaying distinct clinical characteristics. Treatments are mainly based on evidence from common counterparts, which may lead to unsolid benefits considering intertumoral heterogeneity. increasing knowledge profiling has made targeting genetic alterations immune checkpoints a powerful strategy. Additionally, cellular therapy emerged as promising way target tumor cells. this review, we first discuss current status targeted preclinical models cancers, well provide mutational profiles by integrating results existing cohorts. Finally, point out challenges future directions developing agents

Language: Английский

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BRD4-specific PROTAC inhibits basal-like breast cancer partially through downregulating KLF5 expression

Oncogene, Journal Year: 2024, Volume and Issue: 43(39), P. 2914 - 2926

Published: Aug. 20, 2024

Interest in the use of proteolysis-targeting chimeras (PROTACs) cancer therapy has increased recent years. Targeting bromodomain and extra terminal domain (BET) proteins, especially bromodomain-containing protein 4 (BRD4), shown inhibitory effects on basal-like breast (BLBC). However, bioavailability BRD4 PROTACs is restricted by their non-selective biodegradability low tumor-targeting ability. We demonstrated that 6b (BRD4 PROTAC) suppresses BLBC cell growth targeting BRD4, but not BRD2 BRD3, for cereblon (CRBN)-mediated ubiquitination proteasomal degradation. Compound also inhibited expression Krüppel-like factor 5 (KLF5) transcription factor, a key oncoprotein BLBC, controlled BRD4-mediated super-enhancers. Moreover, HCC1806 tumor xenograft mouse model. The combination KLF5 inhibitors showed additive BLBC. These results suggest BRD4-specific PROTAC can effectively inhibit downregulating KLF5, potential as novel therapeutic drug

Language: Английский

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Design, synthesis, and antitumor evaluation of triazolopyridine derivatives as novel inhibitors for BRD4

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 285, P. 117272 - 117272

Published: Jan. 13, 2025

Language: Английский

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AT1, a small molecular degrader of BRD4 based on proteolysis targeting chimera technology alleviates renal fibrosis and inflammation in diabetic nephropathy

Bioorganic Chemistry, Journal Year: 2025, Volume and Issue: 156, P. 108184 - 108184

Published: Jan. 20, 2025

Language: Английский

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Non-enzymatic protein targeting agents as a promising strategy for cancer treatment

Frontiers in Drug Discovery, Journal Year: 2025, Volume and Issue: 5

Published: Jan. 29, 2025

Increased research attention has been brought to non-enzymatic protein targeting agents as a new and effective strategy for advancing cancer treatment. To discover this class of anticancer drugs, two molecular approaches the activities proteins have shown promising experimental, preclinical, clinical results. In first approach, selective known PROteolysis-TArgeting Chimeras (PROTACs) employ innate endogenous degradation machinery in cells proteolyze targeted protein. The combination highly PROTACs exploitation cellular pathways provides opportunity treat diseases that were previously deemed incurable due lack enzymatic proteins. second approach targets protein-protein interactions (PPIs) an alternative route alters functional complexes thus significantly influence cell fitness survival. efficiently identify potential chemical leads these approaches, high-throughput screening (HTS) extremely valuable its ability quickly screen large libraries compounds. review paper, we will provide overview developing anti-cancer impact inhibitors.

Language: Английский

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Unravelling the epigenetic based mechanism in discovery of anticancer phytomedicine: Evidence based studies

Cellular Signalling, Journal Year: 2025, Volume and Issue: unknown, P. 111743 - 111743

Published: March 1, 2025

Language: Английский

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