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Bromodomain inhibitors

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https://www.readbyqxmd.com/read/29329830/theoretical-research-in-structure-characteristics-of-different-inhibitors-and-differences-of-binding-modes-with-cbp-bromodomain
#1
Xue-Song Wang, Qing-Chuan Zheng
The CBP (CREB (cAMP responsive element binding protein) binding protein) bromodomain (BRD) could recognize and bind with acetyl K382 of human tumor suppressor protein p53 which the mutation of encoding gene might cause human cancers. CBP-BRD serves as a promising drug target for several disease pathways and a series of effective drug have been discovered. In this study, molecular dynamics (MD) simulations and molecular mechanics generalized born surface area (MM-GB/SA) approaches were performed to investigate the different binding modes between five inhibitors with CBP-BRD...
December 26, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29312470/combined-inhibition-of-bet-proteins-and-class-i-hdacs-synergistically-induces-apoptosis-in-urothelial-carcinoma-cell-lines
#2
Alexander S Hölscher, Wolfgang A Schulz, Maria Pinkerneil, Günter Niegisch, Michèle J Hoffmann
Background: New efficient therapies for urothelial carcinoma (UC) are urgently required. Small-molecule drugs targeting chromatin regulators are reasonable candidates because these regulators are frequently mutated or deregulated in UC. Indeed, in previous work, Romidepsin, which targets class I histone deacetylases (HDAC), efficiently killed UC cells, but did not elicit canonical apoptosis and affected benign urothelial cells indiscriminately. Combinations of HDAC inhibitors with JQ1, an inhibitor of bromodomain-containing acetylation reader proteins like BRD4, which promote especially the transcription of pro-tumorigenic genes, have shown efficacy in several tumor types...
2018: Clinical Epigenetics
https://www.readbyqxmd.com/read/29303513/in-vitro-modeling-of-hepatocellular-carcinoma-molecular-subtypes-for-anti-cancer-drug-assessment
#3
Hadassa Hirschfield, C Billie Bian, Takaaki Higashi, Shigeki Nakagawa, Tizita Z Zeleke, Venugopalan D Nair, Bryan C Fuchs, Yujin Hoshida
Tractable experimental model that accounts for inter-tumor molecular heterogeneity is a key element of anti-cancer drug development. Hepatocellular carcinoma is known to exhibit highly heterogeneous molecular aberrations across the tumors, including somatic genetic and epigenetic alterations. Previous studies showed that molecular tumor subtypes determined by transcriptome, as a comprehensive functional readout, are reproducibly observed across global patient populations irrespective of geographic and etiological variations...
January 5, 2018: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29290992/oridonin-synergistically-enhances-jq1-triggered-apoptosis-in-hepatocellular-cancer-cells-through-mitochondrial-pathway
#4
Hua-Peng Zhang, Gong-Quan Li, Wen-Zhi Guo, Guang-Hui Chen, Hong-Wei Tang, Bing Yan, Jie Li, Jia-Kai Zhang, Pei-Hao Wen, Zhi-Hui Wang, Jian-Feng Lv, Shui-Jun Zhang
Bromodomain and Extra-Terminal Domain (BET) inhibitors, such as JQ1 have emerged as novel drug candidates and are being enthusiastically pursued in clinical trials for the treatment of cancer. However, many solid cancers are resistance to BET inhibitors. To explore methods for improving the therapeutic potential of BET inhibitors, we investigated the combinational activity of JQ1 with Oridonin, a bioactive molecules derived from Traditional Chinese Medicine in hepatocellular carcinoma (HCC) cells. Our results showed that Oridonin synergistically enhanced the abilities of JQ1 to inhibit cell viability in HCC cells and, significantly augmented JQ1-triggered apoptosis in HCC cells and in HCC cancer stem-like cells...
December 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/29287727/upregulation-of-mcl-1-inhibits-jq1-triggered-anticancer-activity-in-hepatocellular-carcinoma-cells
#5
Hua-Peng Zhang, Gong-Quan Li, Yi Zhang, Wen-Zhi Guo, Jia-Kai Zhang, Jie Li, Jian-Feng Lv, Shui-Jun Zhang
Bromodomains and extra-terminal (BET) proteins inhibitors are promising cancer therapeutic agents. However, tumor cells often develop resistance to BET inhibitors, greatly limiting their therapeutic potential. To study the mechanism underlying the resistance of BET inhibitors in hepatocellular carcinoma (HCC) cells, we herein investigated the impact of BET inhibitor JQ1 on the gene expression of Bcl-2 family members by RNA sequencing analysis, and found that acute treatment with JQ1 triggered upregulation of Mcl-1 in HCCLM3 and BEL7402 cell lines...
December 26, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29262321/bet-bromodomain-inhibition-synergizes-with-parp-inhibitor-in-epithelial-ovarian-cancer
#6
Sergey Karakashev, Hengrui Zhu, Yuhki Yokoyama, Bo Zhao, Nail Fatkhutdinov, Andrew V Kossenkov, Andrew J Wilson, Fiona Simpkins, David Speicher, Dineo Khabele, Benjamin G Bitler, Rugang Zhang
PARP inhibition is known to be an effective clinical strategy in BRCA mutant cancers, but PARP inhibition has not been applied to BRCA-proficient tumors. Here, we show the synergy of BET bromodomain inhibition with PARP inhibition in BRCA-proficient ovarian cancers due to mitotic catastrophe. Treatment of BRCA-proficient ovarian cancer cells with the BET inhibitor JQ1 downregulated the G2-M cell-cycle checkpoint regulator WEE1 and the DNA-damage response factor TOPBP1. Combining PARP inhibitor Olaparib with the BET inhibitor, we observed a synergistic increase in DNA damage and checkpoint defects, which allowed cells to enter mitosis despite the accumulation of DNA damage, ultimately causing mitotic catastrophe...
December 19, 2017: Cell Reports
https://www.readbyqxmd.com/read/29259751/design-synthesis-and-biological-activity-of-1-2-3-triazolobenzodiazepine-bet-bromodomain-inhibitors
#7
Phillip P Sharp, Jean-Marc Garnier, Tamas Hatfaludi, Zhen Xu, David Segal, Kate E Jarman, Hélène Jousset, Alexandra Garnham, John T Feutrill, Anthony Cuzzupe, Peter Hall, Scott Taylor, Carl R Walkley, Dean Tyler, Mark A Dawson, Peter Czabotar, Andrew F Wilks, Stefan Glaser, David C S Huang, Christopher J Burns
A number of diazepines are known to inhibit bromo- and extra-terminal domain (BET) proteins. Their BET inhibitory activity derives from the fusion of an acetyl-lysine mimetic heterocycle onto the diazepine framework. Herein we describe a straightforward, modular synthesis of novel 1,2,3-triazolobenzodiazepines and show that the 1,2,3-triazole acts as an effective acetyl-lysine mimetic heterocycle. Structure-based optimization of this series of compounds led to the development of potent BET bromodomain inhibitors with excellent activity against leukemic cells, concomitant with a reduction in c-MYC expression...
December 14, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29251329/bet-bromodomain-inhibitor-jq1-modulates-microrna-expression-in-thyroid-cancer-cells
#8
Catia Mio, Ketty Conzatti, Federica Baldan, Lorenzo Allegri, Marialuisa Sponziello, Francesca Rosignolo, Diego Russo, Sebastiano Filetti, Giuseppe Damante
Anaplastic thyroid carcinoma (ATC) represents the most lethal thyroid cancer sub-type, currently unresponsive to standard treatments. Recently, bromodomain and extra-terminal (BET) proteins have emerged as attractive therapeutic targets in several diseases, including cancer. In different cancer models, the anti-neoplastic activity of BET inhibitors such as JQ1, I-BET762 and I-BET151 have already been established, due to both direct and indirect effects. miRNAs are 20-22 nucleotide transcriptional regulators which play important roles in proliferation, differentiation and apoptosis...
February 2018: Oncology Reports
https://www.readbyqxmd.com/read/29249691/dual-targeting-of-oncogenic-activation-and-inflammatory-signaling-increases-therapeutic-efficacy-in-myeloproliferative-neoplasms
#9
Maria Kleppe, Richard Koche, Lihua Zou, Peter van Galen, Corinne E Hill, Lauren Dong, Sofie De Groote, Efthymia Papalexi, Amritha V Hanasoge Somasundara, Keith Cordner, Matthew Keller, Noushin Farnoud, Juan Medina, Erin McGovern, Jaime Reyes, Justin Roberts, Matthew Witkins, Franck Rapaport, Julie Teruya-Feldstein, Jun Qi, Raajit Rampal, Bradley E Bernstein, James E Bradner, Ross L Levine
Genetic and functional studies underscore the central role of JAK/STAT signaling in myeloproliferative neoplasms (MPNs). However, the mechanisms that mediate transformation in MPNs are not fully delineated, and clinically utilized JAK inhibitors have limited ability to reduce disease burden or reverse myelofibrosis. Here we show that MPN progenitor cells are characterized by marked alterations in gene regulation through differential enhancer utilization, and identify nuclear factor κB (NF-κB) signaling as a key pathway activated in malignant and non-malignant cells in MPN...
December 1, 2017: Cancer Cell
https://www.readbyqxmd.com/read/29246957/chemoprevention-of-preclinical-breast-and-lung-cancer-with-the-bromodomain-inhibitor-i-bet-762
#10
Di Zhang, Ana S Leal, Sarah Carapellucci, Kayla Zydeck, Michael B Sporn, Karen T Liby
Breast cancer and lung cancer remain the top two leading causes of cancer death in women. Due to limited success in reducing the high mortality of these diseases, new drugs and approaches are desperately needed. Cancer prevention is one such promising strategy that is effective in both preclinical and clinical studies. I-BET 762 is a new bromodomain inhibitor that reversibly targets BET (bromodomain and extra-terminal) proteins and impairs their ability to bind to acetylated lysines on histones, thus interrupting downstream transcription...
December 15, 2017: Cancer Prevention Research
https://www.readbyqxmd.com/read/29246955/a-bet-bromodomain-inhibitor-suppresses-adiposity-associated-malignant-transformation
#11
Debrup Chakraborty, Vanessa Benham, Vladislav Jdanov, Blair Bullard, Ana S Leal, Karen T Liby, Jamie J Bernard
Almost half a million of all new cancers have been attributed to obesity and epidemiological evidence implicates visceral adipose tissue (VAT) and high-fat diets (HFD) in increasing cancer risk. We demonstrated that VAT-derived fibroblast growth factor 2 (FGF2) from mice fed a HFD or obese individuals stimulates the malignant transformation of epithelial cells. Mechanism-based strategies to prevent this VAT-enhanced tumorigenesis have not been explored. Clinical studies have indicated that bromodomain inhibitors have considerable potential as therapeutic agents for cancer by inhibiting the activity of several oncogenes including c-Myc however, their chemopreventive activity is unknown...
December 15, 2017: Cancer Prevention Research
https://www.readbyqxmd.com/read/29240074/bet-bromodomain-inhibitors-synergize-with-atr-inhibitors-in-melanoma
#12
Somsundar Veppil Muralidharan, Berglind Osk Einarsdottir, Joydeep Bhadury, Mattias F Lindberg, Jin Wu, Eric Campeau, Roger Olofsson Bagge, Ulrika Stierner, Lars Ny, Lisa M Nilsson, Jonas A Nilsson
This corrects the article DOI: 10.1038/cddis.2017.383.
December 14, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/29237530/-mechanism-of-action-of-bet-bromodomain-inhibitor-jq1-in-treating-airway-remodeling-in-asthmatic-mice
#13
Xiao-Hua Zhu, Qiu-Gen Li, Jun Wang, Guo-Zhu Hu, Zhi-Qiang Liu, Qing-Hua Hu, Gang Wu
OBJECTIVE: To investigate the molecular mechanism of action of BET bromodomain inhibitor JQ1 in treating airway remodeling in asthmatic mice. METHODS: A total of 24 mice were randomly divided into control group, ovalbumin (OVA)-induced asthma group (OVA group), and JQ1 intervention group (JQ1+OVA group), with 8 mice in each group. OVA sensitization/challenge was performed to establish a mouse model of asthma. At 1 hour before challenge, the mice in the JQ1+OVA group were given intraperitoneal injection of JQ1 solution (50 μg/g)...
December 2017: Zhongguo Dang Dai Er Ke za Zhi, Chinese Journal of Contemporary Pediatrics
https://www.readbyqxmd.com/read/29233295/novel-approaches-to-targeting-brd4
#14
REVIEW
Olesya A Kharenko, Henrik C Hansen
Inhibition of bromo and extra-terminal (BET) bromodomains, including BRD4, has emerged as a new exciting epigenetic target for oncology, in particular. Recently, novel alternatives to the traditional use of reversible small molecules have emerged, including proteolytic targeting BET agents and irreversible binding inhibitors. These alternatives to reversible inhibitors may offer some advantage and can be used as tools to further decipher the underlying biology. Supportive pre-clinical data have these novel approaches bound for clinical development in the near future...
June 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/29228881/unravelling-novel-congeners-from-acetyllysine-mimicking-ligand-targeting-a-lysine-acetyltransferase-pcaf-bromodomain
#15
Venkatesan Suryanarayanan, Sanjeev Kumar Singh
p300/CBP Associated Factor (PCAF) bromodomain (BRD), a lysine acetyltransferases, has emerged as a promising drug target as its dysfunction is linked to onset and progression of several diseases like cancer, diabetes, AIDS etc. In this study, a three featured E-Pharmacophore (ARR) was generated based on acetyllysine mimicking inhibitor of PCAF BRD which is available as co-crystal structure (PDB ID: 5FDZ). It was used for filtering small molecule databases followed by molecular docking and consequently validated using enrichment calculation...
December 11, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29228703/dual-inhibition-of-brd4-and-pi3k-akt-by-sf2523-suppresses-human-renal-cell-carcinoma-cell-growth
#16
Hua Zhu, Jia-Hui Mao, Yin Wang, Dong-Hua Gu, Xiao-Dong Pan, Yuxi Shan, Bing Zheng
Bromodomain-containing protein 4 (BRD4) and PI3K-AKT are both important for renal cell carcinoma (RCC) development and progression. SF2523 is a BRD4 and PI3K-AKT dual inhibitor. The present study demonstrated that SF2523 was cytotoxic and anti-proliferative to established RCC cell lines (786-O and A498) and primary human RCC cells. SF2523 induced activation of caspase and apoptosis in RCC cells. Further, SF2523 disrupted RCC cell cycle progression and inhibited cell migration in vitro. At the signaling level, SF2523 in-activated PI3K-AKT-mTOR, and downregulated BRD4-dependent proteins, Bcl-2 and Myc, in RCC cells...
November 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29212213/the-bromodomain-and-extraterminal-domain-inhibitor-bromosporine-synergistically-reactivates-latent-hiv-1-in-latently-infected-cells
#17
Hanyu Pan, Panpan Lu, Yinzhong Shen, Yanan Wang, Zhengtao Jiang, Xinyi Yang, Yangcheng Zhong, He Yang, Inam Ulla Khan, Muya Zhou, Bokang Li, Ziyu Zhang, Jianqing Xu, Hongzhou Lu, Huanzhang Zhu
The long-lived latent HIV-1 reservoir is the major barrier for complete cure of Acquired Immune Deficiency Syndrome (AIDS). Here we report that a novel bromodomain and extraterminal domain (BET) inhibitor bromosporine which can broadly target BETs, is able to potently reactivate HIV-1 replication in different latency models alone and more powerful when combined with prostratin or TNF-α. Furthermore, the treatment with bromosporine induced HIV-1 full-length transcripts in resting CD4+ T cells from infected individuals with suppressive antiretroviral therapy (ART) ex vivo, with no obvious cytotoxicity or global activation of T cell...
November 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/29212027/melanoma-therapeutic-strategies-that-select-against-resistance-by-exploiting-myc-driven-evolutionary-convergence
#18
Katherine R Singleton, Lorin Crawford, Elizabeth Tsui, Haley E Manchester, Ophelia Maertens, Xiaojing Liu, Maria V Liberti, Anniefer N Magpusao, Elizabeth M Stein, Jennifer P Tingley, Dennie T Frederick, Genevieve M Boland, Keith T Flaherty, Shannon J McCall, Clemens Krepler, Katrin Sproesser, Meenhard Herlyn, Drew J Adams, Jason W Locasale, Karen Cichowski, Sayan Mukherjee, Kris C Wood
Diverse pathways drive resistance to BRAF/MEK inhibitors in BRAF-mutant melanoma, suggesting that durable control of resistance will be a challenge. By combining statistical modeling of genomic data from matched pre-treatment and post-relapse patient tumors with functional interrogation of >20 in vitro and in vivo resistance models, we discovered that major pathways of resistance converge to activate the transcription factor, c-MYC (MYC). MYC expression and pathway gene signatures were suppressed following drug treatment, and then rebounded during progression...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29196562/the-role-of-bromodomain-and-extraterminal-motif-bet-proteins-in-chromatin-structure
#19
Sarah C Hsu, Gerd A Blobel
Bromodomain and extraterminal motif (BET) proteins have been widely investigated for their roles in gene regulation and their potential as therapeutic targets in cancer. Pharmacologic BET inhibitors target the conserved bromodomain-acetyllysine interaction and do not distinguish between BRD2, BRD3, and BRD4. Thus, comparatively little is known regarding the distinct roles played by individual family members, as well as the underlying mechanisms that drive the transcriptional effects of BET inhibitors. Here we review studies regarding the contributions of BET proteins to genome structure and function, including recent work identifying a role for BRD2 as a component of functional and physical chromatin domain boundaries...
December 1, 2017: Cold Spring Harbor Symposia on Quantitative Biology
https://www.readbyqxmd.com/read/29191061/the-identification-of-new-atad2-bromodomain-inhibitors-the-application-of-combined-ligand-and-structure-based-virtual-screening
#20
B Sepehri, R Ghavami
Ligand-based virtual screening (LBVS) and structure-based virtual screening (SBVS) approaches were used to identify new inhibitors for ATAD2 bromodomain. The LBVS approach was used to search 23,129,083 clean compounds to identify compounds similar to an active compound with reported pIC50 equal to 7.2. Based on LBVS results, 19 compounds were selected. To perform SBVS, by applying nine filters on 23,129,083 clean compounds, 1,057,060 compounds were selected. After performing SBVS on these selected compounds with idock software, 16 compounds with the lowest binding energies were selected...
December 1, 2017: SAR and QSAR in Environmental Research
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