Drug Discovery Targeting Bromodomain-Containing Protein 4.
Ontology highlight
ABSTRACT:
SUBMITTER: Liu Z
PROVIDER: S-EPMC5464988 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The bromodomain (BrD) is a conserved structural module found in chromatin- and transcription-associated proteins that acts as the primary reader for acetylated lysine residues. This basic activity endows BrD proteins with versatile functions in the regulation of protein-protein interactions mediating chromatin-templated gene transcription, DNA recombination, replication and repair. Consequently, BrD proteins are involved in the pathogenesis of numerous human diseases. In this Review, we highlight our current understanding of BrD biology, and discuss the latest development of small-molecule inhibitors targeting BrDs as emerging epigenetic therapies for cancer and inflammatory disorders.
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Project description:Bromodomain and extraterminal (BET) proteins bind acetylated lysine residues in histones and nonhistone proteins via tandem bromodomains and regulate chromatin dynamics, cellular processes, and disease procession. Thus targeting BET proteins is a promising strategy for treating various diseases, especially malignant tumors and chronic inflammation. Many pan-BET small-molecule inhibitors have been described, and some of them are in clinical evaluation. Nevertheless, the limited clinical efficacy of the current BET inhibitors is also evident and has inspired the development of new technologies to improve their clinical outcomes and minimize unwanted side effects. In this Review, we summarize the latest protein characteristics and biological functions of BRD4 as an example of BET proteins, analyze the clinical development status and preclinical resistance mechanisms, and discuss recent advances in BRD4-selective inhibitors, dual-target BET inhibitors, proteolysis targeting chimera degraders, and protein-protein interaction inhibitors.
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Project description:The transcriptional regulator BRD4 has been shown to be important for the expression of several oncogenes including MYC. Inhibiting of BRD4 has broad antiproliferative activity in different cancer cell types. The small molecule JQ1 blocks the interaction of BRD4 with acetylated histones leading to transcriptional modulation. Depleting BRD4 via engineered bifunctional small molecules named PROTACs (proteolysis targeting chimeras) represents the next-generation approach to JQ1-mediated BRD4 inhibition. PROTACs trigger BRD4 for proteasomale degradation by recruiting E3 ligases. The aim of this study was therefore to validate the importance of BRD4 as a relevant target in colorectal cancer (CRC) cells and to compare the efficacy of BRD4 inhibition with BRD4 degradation on downregulating MYC expression. JQ1 induced a downregulation of both MYC mRNA and MYC protein associated with an antiproliferative phenotype in CRC cells. dBET1 and MZ1 induced degradation of BRD4 followed by a reduction in MYC expression and CRC cell proliferation. In SW480 cells, where dBET1 failed, we found significantly lower levels of the E3 ligase cereblon, which is essential for dBET1-induced BRD4 degradation. To gain mechanistic insight into the unresponsiveness to dBET1, we generated dBET1-resistant LS174t cells and found a strong downregulation of cereblon protein. These findings suggest that inhibition of BRD4 by JQ1 and degradation of BRD4 by dBET1 and MZ1 are powerful tools for reducing MYC expression and CRC cell proliferation. In addition, downregulation of cereblon may be an important mechanism for developing dBET1 resistance, which can be evaded by incubating dBET1-resistant cells with JQ1 or MZ1.
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Project description:Bromodomain-containing protein 4 (BRD4) is an emerging epigenetic drug target for intractable inflammatory disorders. The lack of highly selective inhibitors among BRD4 family members has stalled the collective understanding of this critical system and the progress toward clinical development of effective therapeutics. Here we report the discovery of a potent BRD4 bromodomain 1 (BD1)-selective inhibitor ZL0590 (52) targeting a unique, previously unreported binding site, while exhibiting significant anti-inflammatory activities in vitro and in vivo. The X-ray crystal structural analysis of ZL0590 in complex with human BRD4 BD1 and the associated mutagenesis study illustrate a first-in-class nonacetylated lysine (KAc) binding site located at the helix αB and αC interface that contains important BRD4 residues (e.g., Glu151) not commonly shared among other family members and is spatially distinct from the classic KAc recognition pocket. This new finding facilitates further elucidation of the complex biology underpinning bromodomain specificity among BRD4 and its protein-protein interaction partners.
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Project description:Acetylation of histone lysine residues is one of the most well-studied post-translational modifications of chromatin, selectively recognized by bromodomain "reader" modules. Inhibitors of the bromodomain and extra terminal domain (BET) family of bromodomains have shown profound anticancer and anti-inflammatory properties, generating much interest in targeting other bromodomain-containing proteins for disease treatment. Herein, we report the discovery of I-BRD9, the first selective cellular chemical probe for bromodomain-containing protein 9 (BRD9). I-BRD9 was identified through structure-based design, leading to greater than 700-fold selectivity over the BET family and 200-fold over the highly homologous bromodomain-containing protein 7 (BRD7). I-BRD9 was used to identify genes regulated by BRD9 in Kasumi-1 cells involved in oncology and immune response pathways and to the best of our knowledge, represents the first selective tool compound available to elucidate the cellular phenotype of BRD9 bromodomain inhibition.
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Project description:Microtubule-associated protein tau is characterized by the fact that it is an intrinsically disordered protein due to its lack of a stable conformation and high flexibility. Intracellular inclusions of fibrillar forms of tau with a β-sheet structure accumulate in the brain of patients with Alzheimer's disease and other tauopathies. Accordingly, detachment of tau from microtubules and transition of tau from a disordered state to an abnormally aggregated state are essential events preceding the onset of tau-related diseases. Many reports have shown that this transition is caused by post-translational modifications, including hyperphosphorylation and acetylation. The misfolded tau is self-assembled and forms a tau oligomer before the appearance of tau inclusions. Animal and pathological studies using human samples have demonstrated that tau oligomer formation contributes to neuronal loss. During the progression of tauopathies, tau seeds are released from cells and incorporated into other cells, leading to the propagation of pathological tau aggregation. Accumulating evidence suggests several potential approaches for blocking tau-mediated toxicity: (1) direct inhibition of pathological tau aggregation and (2) inhibition of tau post-translational modifications that occur prior to pathological tau aggregation, (3) inhibition of tau propagation and (4) stabilization of microtubules. In addition to traditional low-molecular-weight compounds, newer drug discovery approaches such as the development of medium-molecular-weight drugs (peptide- or oligonucleotide-based drugs) and high-molecular-weight drugs (antibody-based drugs) provide alternative pathways to preventing the formation of abnormal tau. Of particular interest are recent studies suggesting that tau droplet formation by liquid-liquid phase separation may be the initial step in aberrant tau aggregation, as well results that implicate roles for tau in dendritic and nuclear functions. Here, we review the mechanisms through which drugs can target tau and consider recent clinical trials for the treatment of tauopathies. In addition, we discuss the utility of these newer strategies and propose future directions for research on tau-targeted therapeutics.
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Project description:To date, the COVID-19 pandemic has claimed over 1 million human lives, infected another 50 million individuals and wreaked havoc on the global economy. The crisis has spurred the ongoing development of drugs targeting its etiological agent, the SARS-CoV-2. Targeting relevant protein-protein interaction interfaces (PPIIs) is a viable paradigm for the design of antiviral drugs and enriches the targetable chemical space by providing alternative targets for drug discovery. In this review, we will provide a comprehensive overview of the theory, methods and applications of PPII-targeted drug development towards COVID-19 based on recent literature. We will also highlight novel developments, such as the successful use of non-native protein-protein interactions as targets for antiviral drug screening. We hope that this review may serve as an entry point for those interested in applying PPIIs towards COVID-19 drug discovery and speed up drug development against the pandemic.
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Project description:The epigenetic reader BRD4 binds acetylated histones and plays a central role in controlling cellular gene transcription and proliferation. Dysregulation of BRD4's activity has been implicated in the pathogenesis of a wide variety of cancers. While blocking BRD4 interaction with acetylated histones using BET inhibitors (BETis) has been tested in clinical trials, many cancers have acquired BETi resistance. However, the underlying mechanisms are poorly understood and BETi resistance remains a pressing clinical problem. We previously showed that BRD4 phosphorylation supports stronger chromatin binding and target oncogene expression. In this study, we discovered that BRD4 is hyperphosphorylated by CDK1 during mitosis and determined the major CDK1 phosphorylation sites in BRD4. Using CRISPR/Cas9 gene editing, we replaced endogenous BRD4 with a non-phosphorylatable mutant and demonstrated that CDK1-mediated BRD4 phosphorylation contributes to BETi resistance. CDK1 over-activation frequently observed in cancers has the potential to cause aberrant BRD4 hyperphosphorylation persisting outside of mitosis to strengthen its target gene binding and confer BETi resistance. We found that dual CDK1 and BET inhibition generates a synergistic effect in killing BETi-resistant cancer cells. Our study therefore suggests that CDK1 inhibition can be employed to overcome tumor BETi resistance and improve treatments for BRD4-associated cancers.
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