Dual-target inhibitors of bromodomain-containing protein 4 (BRD4) in cancer therapy: Current situation and future directions

Jin, Wenke; Tan, Huidan; Wu, Junhao; He, Gu; Liu, Bo

doi:10.1016/j.drudis.2021.08.007

Cited by 20 publications

(15 citation statements)

References 59 publications

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“…For example, in cancer treatment, BETi will be used in combination with other anticancer therapies, such as immunotherapy or radiotherapy, which could lead to the induction of a mixed programmed cell death to suppress tumor growth. And beyond that, dual-target inhibitors could be developed by focusing on the synergistic functions of Brd4 [ 187 ], providing a new way to overcome the barriers inherent to Brd4 inhibition.…”

Section: Discussionmentioning

confidence: 99%

Regulation of programmed cell death by Brd4

Pan

et al. 2022

Cell Death Dis

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Epigenetic factor Brd4 has emerged as a key regulator of cancer cell proliferation. Targeted inhibition of Brd4 suppresses growth and induces apoptosis of various cancer cells. In addition to apoptosis, Brd4 has also been shown to regulate several other forms of programmed cell death (PCD), including autophagy, necroptosis, pyroptosis, and ferroptosis, with different biological outcomes. PCD plays key roles in development and tissue homeostasis by eliminating unnecessary or detrimental cells. Dysregulation of PCD is associated with various human diseases, including cancer, neurodegenerative and infectious diseases. In this review, we discussed some recent findings on how Brd4 actively regulates different forms of PCD and the therapeutic potentials of targeting Brd4 in PCD-related human diseases. A better understanding of PCD regulation would provide not only new insights into pathophysiological functions of PCD but also provide new avenues for therapy by targeting Brd4-regulated PCD.

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Section: Discussionmentioning

confidence: 99%

Regulation of programmed cell death by Brd4

Pan

et al. 2022

Cell Death Dis

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“…Clinical verification is needed to test the efficacy. In addition, the development of dual-target HDAC inhibitors is one of the current research directions ( Jin et al, 2021 ). While remaining active against HDAC, they also act on one or more targets related to AS, which is worth studying in the future.…”

Section: Discussionmentioning

confidence: 99%

New Insight in HDACs: Potential Therapeutic Targets for the Treatment of Atherosclerosis

et al. 2022

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Atherosclerosis (AS) features include progressive hardening and reduced elasticity of arteries. AS is the leading cause of morbidity and mortality. An increasing amount of evidence showed that epigenetic modifications on genes serve are a main cause of several diseases, including AS. Histone deacetylases (HDACs) promote the deacetylation at lysine residues, thereby condensing the chromatin structures and further inhibiting the transcription of downstream genes. HDACs widely affect various physiological and pathological processes through transcriptional regulation or deacetylation of other non-histone proteins. In recent years, the role of HDACs in vascular systems has been revealed, and their effects on atherosclerosis have been widely reported. In this review, we discuss the members of HDACs in vascular systems, determine the diverse roles of HDACs in AS, and reveal the effects of HDAC inhibitors on AS progression. We provide new insights into the potential of HDAC inhibitors as drugs for AS treatment.

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“…Numerous SMIs have successfully passed various stages of clinical trials and been approved by the FDA, including tyrosine kinase inhibitors (TKIs), anaplastic lymphoma kinase inhibitors (ALKs), epidermal growth factor receptor (EGFR), etc [2] . Bromodomain‐containing protein 4 (BRD4) has recently emerged as a promising target for cancer treatment due to its crucial role in regulating gene transcription and maintaining genome stability [3–5] . Moreover, BRD4 expression in cancerous cells, such as glioma, lung cancer, melanoma, etc, is higher than that in normal cells [6] .…”

Section: Introductionmentioning

confidence: 99%

Hydrogen Peroxide‐Inducible PROTACs for Targeted Protein Degradation in Cancer Cells

Fan

Zhou

et al. 2023

ChemBioChem

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Proteolysis‐targeting chimeras (PROTACs) provide a powerful technique to degrade targeted proteins utilizing the cellular ubiquitin‐proteasome system. The major concern is the host toxicity resulting from their poor selectivity. Inducible PROTACs responding to exogenous stimulus, such as light, improve their specificity, but it is difficult for photo‐activation in deep tissues. Herein, we develop H2O2‐inducible PROTAC precursors 2/5, which can be activated by endogenous H2O2 in cancer cells to release the active PROTACs 1/4 to effectively degrade targeted proteins. This results in the intended cytotoxicity towards cancer cells while targeted protein in normal cells remains almost unaffected. The higher Bromodomain‐containing protein 4 (BRD4) degradation activity and cytotoxicity of 2 towards cancer cells is mainly due to the higher endogenous concentration of H2O2 in cancer cells (A549 and H1299), characterized by H2O2‐responsive fluorescence probe 3. Western blot assays and cytotoxicity experiments demonstrate that 2 degrades BRD4 more effectively and is more cytotoxic in H2O2‐rich cancer cells than in H2O2‐deficient normal cells. This method is also extended to estrogen receptor (ER)‐PROTAC precursor 5, showing H2O2‐dependent ER degradation ability. Thus, we establish a novel strategy to induce targeted protein degradation in a H2O2‐dependent way, which has the potential to improve the selectivity of PROTACs.

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Dual-target inhibitors of bromodomain-containing protein 4 (BRD4) in cancer therapy: Current situation and future directions

Cited by 20 publications

References 59 publications

Regulation of programmed cell death by Brd4

Regulation of programmed cell death by Brd4

New Insight in HDACs: Potential Therapeutic Targets for the Treatment of Atherosclerosis

Hydrogen Peroxide‐Inducible PROTACs for Targeted Protein Degradation in Cancer Cells

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