Bromodomain and BET family proteins as epigenetic targets in cancer therapy: their degradation, present drugs, and possible PROTACs

Muddassir, Mohd.; Soni, Kunjal; Sangani, Chetan B.; Alarifi, Abdullah; Afzal, Mohd; Abduh, Naaser A. Y.; Duan, Yongtao; Bhadja, Poonam

doi:10.1039/d0ra07971e

Cited by 9 publications

(4 citation statements)

References 251 publications

(314 reference statements)

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“…In reports on BRD biology, it has been shown that cancer is induced when the transcriptional regulation of genes encoding BRD proteins is unregulated and the transcriptional program of related transcription factors is abnormally driven. ,− Therefore, research on BRD target-based therapeutic strategies is necessary. Leukemia and malignant tumors, such as prostate cancer, malignant melanoma (MM), breast cancer, lymphoma, lung cancer, colon cancer, AML, and neuroblastoma, are susceptible to the aforementioned inhibitors.…”

Section: Application Of Brd-containing Hat Inhibitors In Human Diseasesmentioning

confidence: 99%

Recent Advances on Small-Molecule Bromodomain-Containing Histone Acetyltransferase Inhibitors

Liu

Zhang

et al. 2023

J. Med. Chem.

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In recent years, substantial research has been conducted on molecular mechanisms and inhibitors targeting bromodomains (BRDs) and extra-terminal (BET) family proteins. On this basis, non-BET BRD is gradually becoming a research hot spot. BRDs are abundant in histone acetyltransferase (HAT)associated activating transcription factors, and BRD-containing HATs have been linked to cancer, inflammation, and viral replication. Therefore, the development of BRD-containing HATs as chemical probes is useful for understanding the specific biological roles of BRDs in diseases and drug discovery. Several types of BRD-containing HATs, including CBP/P300, PCAF/ GCN5, and TAF1, are discussed in this context in terms of their structures, functions, and small-molecule inhibitors. Additionally, progress in BRD inhibitors/chemical probes and proteolysis targeting chimeras in terms of drug design, biological activity, and disease application are summarized. These findings provide insights into the development of BRD inhibitors as potential drug candidates for various diseases.

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Section: Application Of Brd-containing Hat Inhibitors In Human Diseasesmentioning

confidence: 99%

Recent Advances on Small-Molecule Bromodomain-Containing Histone Acetyltransferase Inhibitors

Liu

Zhang

et al. 2023

J. Med. Chem.

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“…BRD9 is the BRD-containing subunit of the BAF (BRG-/BRM-associated factor) and its close homolog BRD7 is the subunit of PBAF (polybromo-associated BAF) 26 , 27 . BAF and PBAF are two variants of the SWI/SNF complex, which regulate gene expression, DNA replication, and DNA repair 28 , 29 . Overexpression of BRD7/9 can lead to cancers development.…”

Section: Introductionmentioning

confidence: 99%

PROTACs for BRDs proteins in cancer therapy: a review

Wang

Zhang

Yang

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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BRDs proteins that recognise chromatin acetylation regulate gene expression, are epigenetic readers and master transcription coactivators. BRDs proteins are now emerging as targets for new therapeutic development. Blocking the function of any of BRDs proteins can be a control agent for diseases, such as cancer. Traditional drugs like enzyme inhibitors and protein–protein inhibitors have many limitations. The therapeutic efficacy of them remains to be proven. Recently, Proteolysis-Targeting Chimaeras (PROTACs) have become an advanced tool in therapeutic intervention as they remove disease-causing proteins. Extremely potent and efficacious small-molecule PROTACs of the BRDs proteins, based on available, potent, and selective BRDs inhibitors, have been reported. This review presents a comprehensive overview of the development of PROTACs for BRDs proteins regulation in cancer, and the chances and challenges associated with this area are also highlighted.

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“…[16] This family of protein over the years have been a therapeutic target for several diseases such as cancer and inflammation. [17,18] BET proteins are characterized by dual bromodomains (BD1 and BD2) such as BRD2, BRD3, BRD4, and BRDT. BETs are known to bind the acetylated lysine on histone complexes of proteins to promote recruitment and stabilization, a rate-limiting step in gene expression.…”

Section: Introductionmentioning

confidence: 99%

“…The Bromodomain and extra‐terminal domain (BET) protein family consists of a group of proteins that specializes in recognizing acetylated lysine on chromatin [16] . This family of protein over the years have been a therapeutic target for several diseases such as cancer and inflammation [17,18] . BET proteins are characterized by dual bromodomains (BD1 and BD2) such as BRD2, BRD3, BRD4, and BRDT.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Insights into the Selective Dual BET and PLK1 Inhibitory Activity of a Novel Benzamide Compound in Castration‐Resistant Prostrate Cancer

Akawa

Subair

Omolabi

et al. 2021

Chemistry & Biodiversity

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Though multifactorial, BET and PLK1 proteins have been found to be key players in the oncogenic process leading to castration-resistant prostate cancer through regulation of AR and MYC-mediated transcription. Hence, dual inhibition of these proteins appears to be an auspicious approach for CRPC therapy. WNY0824 has been reported to exhibit nanomolar range inhibition as well as significant anti-proliferative activity on AR-positive CRPC cells in vitro. However, structural, and mechanistic events associated with its dual inhibitory and antiproliferative mechanisms remain unclear. Utilizing integrative computer-assisted atomistic techniques, analyses revealed that the dual-inhibitory activity of WNY0824 against BRD4 and PLK1 proteins is mediated by conserved residues present in the binding cavities of both proteins which are shown to elicit various strong intermolecular interactions and thus favour binding affinity. Also, binding orientation of the ligand at the protein binding cavities allowed for important hydrophobic interactions which resulted in high binding free energy of À 42.50 kcal/mol and À 51.64 kcal/mol towards BRD4 and PLK1, respectively. While van der Waals interactions are very important to ligand binding in BRD4-WNY complex, electrostatic interactions are pertinent to PLK1-WNY complex. Intriguingly, WNY0824 triggered conformational alterations in both proteins through increased structural instability, decreased structural compactness and mitigation in exposure of residues to solvent surface area. Consequently, critical interactions peculiar to the oncogenic activities of BRD4 and PLK1 were inhibited, a phenomenon that results in an antagonism of CRPC progression. The mechanistic insights presented in this report would further assist in the structure-based design of improved inhibitors useful in CRPC therapy.

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Bromodomain and BET family proteins as epigenetic targets in cancer therapy: their degradation, present drugs, and possible PROTACs

Abstract: Alteration in the pattern of epigenetic marking leads to cancer, neurological disorders, inflammatory problems etc.

Cited by 9 publications

References 251 publications

Recent Advances on Small-Molecule Bromodomain-Containing Histone Acetyltransferase Inhibitors

Recent Advances on Small-Molecule Bromodomain-Containing Histone Acetyltransferase Inhibitors

PROTACs for BRDs proteins in cancer therapy: a review

Mechanistic Insights into the Selective Dual BET and PLK1 Inhibitory Activity of a Novel Benzamide Compound in Castration‐Resistant Prostrate Cancer

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