Structure-based design, synthesis and in vitro antiproliferative effects studies of novel dual BRD4/HDAC inhibitors

Shao, Mingfeng; He, Libang; Li, Zheng; Huang, Lei; Zhou, Yuanyuan; Wang, Taijing; Chen, Yong; Shen, Mingsheng; Wang, Fang; Yang, Zhuang; Chen, Lijuan

doi:10.1016/j.bmcl.2017.07.054

Cited by 47 publications

(33 citation statements)

References 21 publications

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“…Bromodomains received also some interest in this regard, as some dual bromodomain/kinase inhibitors were investigated [71][72][73][74]. Of particular relevance to the current work are the attempts to design dual HDAC/BRD epigenetic inhibitors [75][76][77][78][79]. In all of the reported studies, the rationale was to change the cap group of HDACi, mostly SAHA, to a reported BRD4 inhibiting pharmacophore.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and biological evaluation of dual targeting inhibitors of histone deacetylase 6/8 and bromodomain BRPF1

Ghazy

Zeyen

Herp

et al. 2020

European Journal of Medicinal Chemistry

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Histone modifying proteins, specifically histone deacetylases (HDACs) and bromodomains, have emerged as novel promising targets for anticancer therapy. In the current work, based on available crystal structures and docking studies, we designed dual inhibitors of both HDAC6/8 and the bromodomain and PHD finger containing protein 1 (BRPF1). Biochemical and biophysical tests showed that compounds 23a,b and 37 are nanomolar inhibitors of both target proteins. Detailed structure-activity relationships were deduced for the synthesized inhibitors which were supported by extensive docking and molecular dynamics studies. Cellular testing in acute myeloid leukemia (AML) cells showed only a weak effect, most probably because of the poor permeability of the inhibitors. We also aimed to analyse the target engagement and the cellular activity of the novel inhibitors by determining the protein acetylation levels in cells by western blotting (tubulin vs histone acetylation), and by assessing their effects on various cancer cell lines.

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Section: Introductionmentioning

confidence: 99%

Design, synthesis, and biological evaluation of dual targeting inhibitors of histone deacetylase 6/8 and bromodomain BRPF1

Ghazy

Zeyen

Herp

et al. 2020

European Journal of Medicinal Chemistry

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“…These and other works provide evidence to support the idea of combined therapy, but some researchers went further and tried to produce a single molecule able to inhibit both HDAC and BET protein [83,84,85,86]. Basically, the idea is to combine the active group of BET and HDAC inhibitors into one molecule in order to develop new and more efficient drugs.…”

Section: Molecular Interplay Between Hdac and Bet Proteins And Duamentioning

confidence: 99%

“…Zhang et al [83] have synthetized a series of novel 3,5-dimethylisoxazole derivatives as BRD4/HDAC dual inhibitors, demonstrating their antiproliferative effects on chronic myeloid leukemia (CML) and AML cell lines. Shao et al [84] reported a 3,4,5-trihydroxy-transstilbene with a hydroxamate group to be more effective than combination of BETi and HDACi in killing c-Myc-induced murine cell lymphoma.…”

Section: Molecular Interplay Between Hdac and Bet Proteins And Duamentioning

confidence: 99%

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Inhibition of BET Proteins and Histone Deacetylase (HDACs): Crossing Roads in Cancer Therapy

Manzotti

Ciarrocchi

Sancisi

2019

Cancers

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Histone DeACetylases (HDACs) are enzymes that remove acetyl groups from histones and other proteins, regulating the expression of target genes. Pharmacological inhibition of these enzymes re-shapes chromatin acetylation status, confusing boundaries between transcriptionally active and quiescent chromatin. This results in reinducing expression of silent genes while repressing highly transcribed genes. Bromodomain and Extraterminal domain (BET) proteins are readers of acetylated chromatin status and accumulate on transcriptionally active regulatory elements where they serve as scaffold for the building of transcription-promoting complexes. The expression of many well-known oncogenes relies on BET proteins function, indicating BET inhibition as a strategy to counteract their activity. BETi and HDACi share many common targets and affect similar cellular processes to the point that combined inhibition of both these classes of proteins is regarded as a strategy to improve the effectiveness of these drugs in cancer. In this work, we aim to discuss the molecular basis of the interplay between HDAC and BET proteins, pointing at chromatin acetylation as a crucial node of their functional interaction. We will also describe the state of the art of their dual inhibition in cancer therapy. Finally, starting from their mechanism of action we will provide a speculative perspective on how these drugs may be employed in combination with standard therapies to improve effectiveness and/or overcome resistance.

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“…Combining BETi and HDACi repressed Ras at the protein level as well as phosphorylation of MEK and ERK1/2, indicating that changes in Ras function may underlie the synergy between the two agents. Recently, a dual HDAC/BRD4 inhibitor has been developed that inhibits growth of AML and chronic myelogenous leukemia (CML), in vitro (198–200). These studies suggest that either combining HDACi and BETi or use of a dual HDAC/BRD4 inhibitor may have efficacy in at least two subtypes of breast cancer.…”

Section: Alternative Bet Protein Targeting Mechanismsmentioning

confidence: 99%

Targeting bromodomain and extraterminal proteins in breast cancer

Sahni

Keri

2018

Pharmacological Research

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Breast cancer is a collection of distinct tumor subtypes that are driven by unique gene expression profiles. These transcriptomes are controlled by various epigenetic marks that dictate which genes are expressed and suppressed. During carcinogenesis, extensive restructuring of the epigenome occurs, including aberrant acetylation, alteration of methylation patterns, and accumulation of epigenetic readers at oncogenes. As epigenetic alterations are reversible, epigenome-modulating drugs could provide a mechanism to silence numerous oncogenes simultaneously. Here, we review the impact of inhibitors of the Bromodomain and Extraterminal (BET) family of epigenetic readers in breast cancer. These agents, including the prototypical BET inhibitor JQ1, have been shown to suppress a variety of oncogenic pathways while inducing minimal, if any, toxicity in models of several subtypes of breast cancer. BET inhibitors also synergize with multiple approved anti-cancer drugs, providing a greater response in breast cancer cell lines and mouse models than either single agent. The combined findings of the studies discussed here provide an excellent rationale for the continued investigation of the utility of BET inhibitors in breast cancer.

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Structure-based design, synthesis and in vitro antiproliferative effects studies of novel dual BRD4/HDAC inhibitors

Cited by 47 publications

References 21 publications

Design, synthesis, and biological evaluation of dual targeting inhibitors of histone deacetylase 6/8 and bromodomain BRPF1

Design, synthesis, and biological evaluation of dual targeting inhibitors of histone deacetylase 6/8 and bromodomain BRPF1

Inhibition of BET Proteins and Histone Deacetylase (HDACs): Crossing Roads in Cancer Therapy

Targeting bromodomain and extraterminal proteins in breast cancer

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