Novel strategies targeting bromodomain-containing protein 4 (BRD4) for cancer drug discovery

Liang, Dailin; Yu, Yifan; Ma, Zonghui

doi:10.1016/j.ejmech.2020.112426

Cited by 47 publications

(17 citation statements)

References 91 publications

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“…Moreover, the increased BRD4 was also observed in the tumor whole blood and cell lines. BRD4 serves as a tumor promoter in multiple cancers and takes part in the cellular activities to boost the incontrollable growth of tumor cells [24]. Recent evidence has further added the complexity of BRD4's role in cancer, indicating that this protein has additional nontranscriptional functions that affect processes such as DNA damage repair, checkpoint activation, or telomere homeostasis.…”

Section: Discussionmentioning

confidence: 99%

miR-124a Involves in the Regulation of Wnt/β-Catenin and P53 Pathways to Inhibit Abdominal Aortic Aneurysm via Targeting BRD4

et al. 2022

Computational and Mathematical Methods in Medicine

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Background. Abdominal aortic aneurysm (AAA) belongs to a progressive, gradual aortic rupture, which can lead to death without surgical intervention. The key factors regulating the occurrence and progress of AAA are not clear. Increasing studies have indicated that microRNA (miRNA) plays an important role in cancer development. miR-124a serves as a tumor suppressor in several neoplasms, and its upregulation can greatly inhibit the life activities such as malignant growth and migration of tumor cells. Aim. The objective of this study is to explore the association of miR-124a with AAA and to uncover the regulated mechanism of miR-124a on AAA progression. Methods. The specimens from the AAA patients were used for observing the miR-124a expression, and human aortic endothelial cells (hAoECs) were treated with AngII to establish the AAA cell models. The quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), CCK-8, transwell assay, flow cytometry assay, and western blot were conducted to unearth the regulation mechanism of miR-124a on AAA, and the dual-luciferase reporter assay was employed to investigate the downstream target of miR-124a. Results. miR-124a was significantly downregulated in the whole blood of the patients, and the decreased miR-124a was also observed in AAA cell models. Overexpressing miR-124a could effectively inhibit the proliferation and migration and promote the apoptosis of the AAA cells. The dual-luciferase reporter assay confirmed that BRD4 was a downstream target of miR-124a, and BRD4 upregulation could obviously reverse the effects of miR-124a on the phenotype of AAA cells. Moreover, it was found that miR-124a could regulate the activities of Wnt/β-catenin and P53 pathways via targeting the BRD4. Conclusion. Our data suggested that miR-124a could regulate the activities of Wnt/β-catenin and P53 to suppress the AAA progression via targeting the BRD4.

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Section: Discussionmentioning

confidence: 99%

miR-124a Involves in the Regulation of Wnt/β-Catenin and P53 Pathways to Inhibit Abdominal Aortic Aneurysm via Targeting BRD4

et al. 2022

Computational and Mathematical Methods in Medicine

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“…The pool of BRD4 inhibitors continues to grow, with most identified through fragment or structure-based drug design based on properties of known BRD4 inhibitors. [23][24][25][26][27] Additionally, a recent review 28 identified three novel strategies in targeting BRD4, including bivalent BRD4 inhibitors, proteolytic targeting chimeric molecules and re-purposing of kinase inhibitors. The selectivity of inhibitors is also being targeted.…”

Section: Introductionmentioning

confidence: 99%

Structural variation of protein–ligand complexes of the first bromodomain of BRD4

2021

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“…Various lines of evidence have suggested that BRD4 facilitates malignant phenotypes in diverse cancer contexts. In particular, as an epigenetic reader of the histone code, BRD4 recognizes H3K27ac through the BET domain and recruits transcriptional regulators to establish SEs [45]. To date, many small-molecule BRD4 inhibitors have been discovered, some of which are in clinical trials for the treatment of different diseases.…”

Section: Discussionmentioning

confidence: 99%

Discovery of a Novel Aminocyclopropenone Compound That Inhibits BRD4-Driven Nucleoporin NUP210 Expression and Attenuates Colorectal Cancer Growth

Kondo

Mishiro

Iwashima

et al. 2022

Cells

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Epigenetic deregulation plays an essential role in colorectal cancer progression. Bromodomains are epigenetic “readers” of histone acetylation. Bromodomain-containing protein 4 (BRD4) plays a pivotal role in transcriptional regulation and is a feasible drug target in cancer cells. Disease-specific elevation of nucleoporin, a component of the nuclear pore complex (NPC), is a determinant of cancer malignancy, but BRD4-driven changes of NPC composition remain poorly understood. Here, we developed novel aminocyclopropenones and investigated their biological effects on cancer cell growth and BRD4 functions. Among 21 compounds developed here, we identified aminocyclopropenone 1n (ACP-1n) with the strongest inhibitory effects on the growth of the cancer cell line HCT116. ACP-1n blocked BRD4 functions by preventing its phase separation ability both in vitro and in vivo, attenuating the expression levels of BRD4-driven MYC. Notably, ACP-1n significantly reduced the nuclear size with concomitant suppression of the level of the NPC protein nucleoporin NUP210. Furthermore, NUP210 is in a BRD4-dependent manner and silencing of NUP210 was sufficient to decrease nucleus size and cellular growth. In conclusion, our findings highlighted an aminocyclopropenone compound as a novel therapeutic drug blocking BRD4 assembly, thereby preventing BRD4-driven oncogenic functions in cancer cells. This study facilitates the development of the next generation of effective and potent inhibitors of epigenetic bromodomains and extra-terminal (BET) protein family.

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Novel strategies targeting bromodomain-containing protein 4 (BRD4) for cancer drug discovery

Cited by 47 publications

References 91 publications

miR-124a Involves in the Regulation of Wnt/β-Catenin and P53 Pathways to Inhibit Abdominal Aortic Aneurysm via Targeting BRD4

miR-124a Involves in the Regulation of Wnt/β-Catenin and P53 Pathways to Inhibit Abdominal Aortic Aneurysm via Targeting BRD4

Structural variation of protein–ligand complexes of the first bromodomain of BRD4

Discovery of a Novel Aminocyclopropenone Compound That Inhibits BRD4-Driven Nucleoporin NUP210 Expression and Attenuates Colorectal Cancer Growth

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