Structure-Based Discovery and Development of a Series of Potent and Selective Bromodomain and Extra-Terminal Protein Inhibitors

Hu, Jianping; Tian, Changqing; Damaneh, Mohammadali Soleimani; Li, Yanlian; Cao, Danyan; Lv, Kaikai; Yu, Ting; Meng, Tao; Chen, Danqi; Wang, Xin; Chen, Lin; Li, Jian; Song, Shanshan; Huan, Xia‐Juan; Qin, Lianju; Shen, Jingkang; Wang, Ying-Qing; Miao, Ze‐Hong; Xiong, Bing

doi:10.1021/acs.jmedchem.9b01094

Cited by 32 publications

(45 citation statements)

References 49 publications

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“…A subset of infected A549 cells were additionally treated with the BRD4 inhibitor ZL0454 (10 µM) beginning 12 h before infection. ZL0454 has been shown to effectively and specifically target the bromodomains of BRD4, with minimal cross-reactivity with other bromodomain proteins [19,21]. Control cells were treated with DMSO, and left uninfected.…”

Section: Resultsmentioning

confidence: 99%

“…In this study, we apply native immunoprecipitation (IP) of endogenous BRD4 complexes and high-resolution Online parallel accumulation-serial fragmentation mass spectrometry (PASEF-MS) [18] to address this knowledge gap by examining the BRD4 interactome and its dynamic changes in response to RSV infection. We also measure the dependence of these interactions on BRD4's bromodomains by perturbing the complex with the small molecule bromodomain inhibitor, ZL0454 [19][20][21]. Our results demonstrate that BRD4 recruits several inflammation-modulating transcription factors during RSV infection, including β-catenin of the Wnt-signaling pathway and c-JUN (JUN) and Fos-Related Antigen 1 (FOSL1) of the AP1 complex.…”

Section: Introductionmentioning

confidence: 96%

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Discovery of RSV-Induced BRD4 Protein Interactions Using Native Immunoprecipitation and Parallel Accumulation—Serial Fragmentation (PASEF) Mass Spectrometry

Mann

Roberts

Zhu

et al. 2021

Viruses

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Respiratory Syncytial Virus (RSV) causes severe inflammation and airway pathology in children and the elderly by infecting the epithelial cells of the upper and lower respiratory tract. RSV replication is sensed by intracellular pattern recognition receptors upstream of the IRF and NF-κB transcription factors. These proteins coordinate an innate inflammatory response via Bromodomain-containing protein 4 (BRD4), a protein that functions as a scaffold for unknown transcriptional regulators. To better understand the pleiotropic regulatory function of BRD4, we examine the BRD4 interactome and identify how RSV infection dynamically alters it. To accomplish these goals, we leverage native immunoprecipitation and Parallel Accumulation—Serial Fragmentation (PASEF) mass spectrometry to examine BRD4 complexes isolated from human alveolar epithelial cells in the absence or presence of RSV infection. In addition, we explore the role of BRD4’s acetyl-lysine binding bromodomains in mediating these interactions by using a highly selective competitive bromodomain inhibitor. We identify 101 proteins that are significantly enriched in the BRD4 complex and are responsive to both RSV-infection and BRD4 inhibition. These proteins are highly enriched in transcription factors and transcriptional coactivators. Among them, we identify members of the AP1 transcription factor complex, a complex important in innate signaling and cell stress responses. We independently confirm the BRD4/AP1 interaction in primary human small airway epithelial cells. We conclude that BRD4 recruits multiple transcription factors during RSV infection in a manner dependent on acetyl-lysine binding domain interactions. This data suggests that BRD4 recruits transcription factors to target its RNA processing complex to regulate gene expression in innate immunity and inflammation.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Discovery of RSV-Induced BRD4 Protein Interactions Using Native Immunoprecipitation and Parallel Accumulation—Serial Fragmentation (PASEF) Mass Spectrometry

Mann

Roberts

Zhu

et al. 2021

Viruses

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“…Bromodomain-containing proteins (BCPs) can decipher the acetylation code of proteins via binding to their acetylated lysine (KAc) residues, which further modulates acetylation signal transduction and produces diverse physiological functions [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. BCPs are divided into eight subfamilies containing the bromodomain and extra-terminal domain (BET) subfamily [ 11 , 12 ]. The BET subfamily [ 12 ] consists of BRD2 [ 13 ], BRD3 [ 14 ], BRD4 [ 12 , 15 ] and BRD testis-specific protein BRDT [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

“…BCPs are divided into eight subfamilies containing the bromodomain and extra-terminal domain (BET) subfamily [ 11 , 12 ]. The BET subfamily [ 12 ] consists of BRD2 [ 13 ], BRD3 [ 14 ], BRD4 [ 12 , 15 ] and BRD testis-specific protein BRDT [ 16 , 17 ]. The BET protein family is highly similar in structure and function and is mainly composed of BD1, BD2 and ET domains and CHAT and CTM functional domains.…”

Section: Introductionmentioning

confidence: 99%

“…In 2019, Hu et al performed further lead optimization to generate a novel potent series of bromodomain and extra-terminal (BET) inhibitors with a (1,2,4-triazol-5-yl)-3,4-dihydroquinoxalin-2(1H)-one structure, and they found that compound 19 is a potential BET protein drug candidate for the treatment of cancer [ 12 ]. However, what effects do the potent and selective inhibitors binding to BRD4 have on the active site?…”

Section: Introductionmentioning

confidence: 99%

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Molecular Dynamic Simulations of Bromodomain and Extra-Terminal Protein 4 Bonded to Potent Inhibitors

Chen

Geng

et al. 2021

Molecules

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Bromodomain and extra-terminal domain (BET) subfamily is the most studied subfamily of bromodomain-containing proteins (BCPs) family which can modulate acetylation signal transduction and produce diverse physiological functions. Thus, the BET family can be treated as an alternative strategy for targeting androgen-receptor (AR)-driven cancers. In order to explore the effect of inhibitors binding to BRD4 (the most studied member of BET family), four 150 ns molecular dynamic simulations were performed (free BRD4, Cpd4-BRD4, Cpd9-BRD4 and Cpd19-BRD4). Docking studies showed that Cpd9 and Cpd19 were located at the active pocket, as well as Cpd4. Molecular dynamics (MD) simulations indicated that only Cpd19 binding to BRD4 can induce residue Trp81-Ala89 partly become α-helix during MD simulations. MM-GBSA calculations suggested that Cpd19 had the best binding effect with BRD4 followed by Cpd4 and Cpd9. Computational alanine scanning results indicated that mutations in Phe83 made the greatest effects in Cpd9-BRD4 and Cpd19-BRD4 complexes, showing that Phe83 may play crucial roles in Cpd9 and Cpd19 binding to BRD4. Our results can provide some useful clues for further BCPs family search.

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Targeting CBX3 with a Dual BET/PLK1 Inhibitor Enhances the Antitumor Efficacy of CDK4/6 Inhibitors in Prostate Cancer

Liang,

Yang,

Zeng

et al. 2023

Advanced Science

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The development of castration‐resistant prostate cancer (CRPC) is a significant factor that reduces life expectancy among patients with prostate cancer. Previously, it is reported that CDK4/6 inhibitors can overcome the resistance of CRPC to BET inhibitors by destabilizing BRD4, suggesting that the combination of CDK4/6 inhibitors and BET inhibitors is a promising approach for treating CRPC. In this study, candidates that affect the combined antitumor effect of CDK4/6 inhibitors and BET inhibitors on CRPC is aimed to examine. The data demonstrates that CBX3 is abnormally upregulated in CDK4/6 inhibitors‐resistant cells. CBX3 is almost positively correlated with the cell cycle in multiple malignancies and is downregulated by BET inhibitors. Mechanistically, it is showed that CBX3 is transcriptionally upregulated by BRD4 in CRPC cells. Moreover, it is demonstrated that CBX3 modulated the sensitivity of CRPC to CDK4/6 inhibitors by binding with RB1 to release E2F1. Furthermore, it is revealed that PLK1 phosphorylated CBX3 to enhance the interaction between RB1 and CBX3, and desensitize CRPC cells to CDK4/6 inhibitors. Given that BRD4 regulates CBX3 expression and PLK1 affects the binding between RB1 and CBX3, it is proposed that a dual BRD4/PLK1 inhibitor can increase the sensitivity of CRPC cells to CDK4/6 inhibitors partially through CBX3.

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Structure-Based Discovery and Development of a Series of Potent and Selective Bromodomain and Extra-Terminal Protein Inhibitors

Cited by 32 publications

References 49 publications

Discovery of RSV-Induced BRD4 Protein Interactions Using Native Immunoprecipitation and Parallel Accumulation—Serial Fragmentation (PASEF) Mass Spectrometry

Discovery of RSV-Induced BRD4 Protein Interactions Using Native Immunoprecipitation and Parallel Accumulation—Serial Fragmentation (PASEF) Mass Spectrometry

Molecular Dynamic Simulations of Bromodomain and Extra-Terminal Protein 4 Bonded to Potent Inhibitors

Targeting CBX3 with a Dual BET/PLK1 Inhibitor Enhances the Antitumor Efficacy of CDK4/6 Inhibitors in Prostate Cancer

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