Structural features and inhibitors of bromodomains

Meslamani, Jamel; Smith, Steven G.; Sánchez, Roberto; Zhou, Ming‐Ming

doi:10.1016/j.ddtec.2016.09.001

Cited by 23 publications

(22 citation statements)

References 64 publications

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“…BD2-specific histidine (His433), Val435, Pro430, and Lys374 replace Asp144, Ile146, Lys141, and Gln85, respectively, leading to a narrower binding pocket as well as altered polarity and hydrophobicity compared to BD1 72,80,157,201 (Figure 3).…”

Section: Bromodomain-selective Bindingmentioning

confidence: 99%

Inhibitors of bromodomain and extra‐terminal proteins for treating multiple human diseases

Kulikowski

Rakai

Wong

2020

Medicinal Research Reviews

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Clinical development of bromodomain and extra‐terminal (BET) protein inhibitors differs from the traditional course of drug development. These drugs are simultaneously being evaluated for treating a wide spectrum of human diseases due to their novel mechanism of action. BET proteins are epigenetic “readers,” which play a primary role in transcription. Here, we briefly describe the BET family of proteins, of which BRD4 has been studied most extensively. We discuss BRD4 activity at latent enhancers as an example of BET protein function. We examine BRD4 redistribution and enhancer reprogramming in embryonic development, cancer, cardiovascular, autoimmune, and metabolic diseases, presenting hallmark studies that highlight BET proteins as attractive targets for therapeutic intervention. We review the currently available approaches to targeting BET proteins, methods of selectively targeting individual bromodomains, and review studies that compare the effects of selective BET inhibition to those of pan‐BET inhibition. Lastly, we examine the current clinical landscape of BET inhibitor development.

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Section: Bromodomain-selective Bindingmentioning

confidence: 99%

Inhibitors of bromodomain and extra‐terminal proteins for treating multiple human diseases

Kulikowski

Rakai

Wong

2020

Medicinal Research Reviews

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“…BET proteins, such as BRD4, contain two bromodomains (BD1 and BD2), which are druggable targets (7, 8). JQ1 (thieno-triazolo-1,4-diazepine) is the first published small molecule that binds competitively to bromodomains (7, 9). A majority of these BET inhibitors (BETi) block both BD1 and BD2, while others may specifically inhibit BD1 or BD2 (10).…”

Section: Introductionmentioning

confidence: 99%

Vitamin C Sensitizes Melanoma to BET Inhibitors

et al. 2018

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Bromodomain and extraterminal inhibitors (BETi) are promising cancer therapies, yet prominent side effects of BETi at effective doses have been reported in phase I clinical trials. Here, we screened a panel of small molecules targeting epigenetic modulators against human metastatic melanoma cells. Cells were pretreated with or without ascorbate (vitamin C), which promotes DNA demethylation and subsequently changes the sensitivity to drugs. Top hits were structurally unrelated BETi, including JQ1, I-BET151, CPI-203, and BI-2536. Ascorbate enhanced the efficacy of BETi by decreasing acetylation of histone H4, but not H3, while exerting no effect on the expression of BRD proteins. Histone acetyltransferase 1 (HAT1), which catalyzes H4K5ac and H4K12ac, was downregulated by ascorbate mainly via the TET-mediated DNA hydroxymethylation pathway. Loss of H4ac, especially H4K5ac and H4K12ac, disrupted the interaction between BRD4 and H4 by which ascorbate and BETi blocked the binding of BRD4 to acetylated histones. Cotreatment with ascorbate and JQ1 induced apoptosis and inhibited proliferation of cultured melanoma cells. Ascorbate deficiency as modeled in mice diminished the treatment outcome of JQ1 for melanoma tumorgraft. In contrast, ascorbate supplementation lowered the effective dose of JQ1 needed to successfully inhibit melanoma tumors in mice. On the basis of our findings, future clinical trials with BETi should consider ascorbate levels in patients. Furthermore, ascorbate supplementation might help reduce the severe side effects that arise from BETi therapy by reducing the dosage necessary for treatment. This study shows that ascorbate can enhance the efficacy of BET inhibitors, providing a possible clinical solution to challenges arising in phase I trials from the dose-dependent side effects of this class of epigenetic therapy. .

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“…Bromodomain and Histone interactions involve binding of Bromo domains to acetylated histones, and thereby, bromodomains mediate the binding of several protein complexes such as histone acetytransferases, chromatin remodeling complexes, specific and general transcription factors, etc., to chromatin and have role in gene activation and regulation [ 38 ]. Because of their implications in cancer and inflammation, several groups have been working to design drugs targeting this PPI [ 39 ]. Likewise, P53 is a tumor suppressor gene which is inhibited after its binding to MDM2.…”

Section: Resultsmentioning

confidence: 99%

SMMPPI: a machine learning-based approach for prediction of modulators of protein–protein interactions and its application for identification of novel inhibitors for RBD:hACE2 interactions in SARS-CoV-2

Gupta

Mohanty

2021

Briefings in Bioinformatics

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Small molecule modulators of protein–protein interactions (PPIs) are being pursued as novel anticancer, antiviral and antimicrobial drug candidates. We have utilized a large data set of experimentally validated PPI modulators and developed machine learning classifiers for prediction of new small molecule modulators of PPI. Our analysis reveals that using random forest (RF) classifier, general PPI Modulators independent of PPI family can be predicted with ROC-AUC higher than 0.9, when training and test sets are generated by random split. The performance of the classifier on data sets very different from those used in training has also been estimated by using different state of the art protocols for removing various types of bias in division of data into training and test sets. The family-specific PPIM predictors developed in this work for 11 clinically important PPI families also have prediction accuracies of above 90% in majority of the cases. All these ML-based predictors have been implemented in a freely available software named SMMPPI for prediction of small molecule modulators for clinically relevant PPIs like RBD:hACE2, Bromodomain_Histone, BCL2-Like_BAX/BAK, LEDGF_IN, LFA_ICAM, MDM2-Like_P53, RAS_SOS1, XIAP_Smac, WDR5_MLL1, KEAP1_NRF2 and CD4_gp120. We have identified novel chemical scaffolds as inhibitors for RBD_hACE PPI involved in host cell entry of SARS-CoV-2. Docking studies for some of the compounds reveal that they can inhibit RBD_hACE2 interaction by high affinity binding to interaction hotspots on RBD. Some of these new scaffolds have also been found in SARS-CoV-2 viral growth inhibitors reported recently; however, it is not known if these molecules inhibit the entry phase.

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Structural features and inhibitors of bromodomains

Cited by 23 publications

References 64 publications

Inhibitors of bromodomain and extra‐terminal proteins for treating multiple human diseases

Inhibitors of bromodomain and extra‐terminal proteins for treating multiple human diseases

Vitamin C Sensitizes Melanoma to BET Inhibitors

SMMPPI: a machine learning-based approach for prediction of modulators of protein–protein interactions and its application for identification of novel inhibitors for RBD:hACE2 interactions in SARS-CoV-2

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