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Bet inhibitor

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https://www.readbyqxmd.com/read/28535045/bet-bromodomain-inhibitors-with-one-step-synthesis-discovered-from-virtual-screen
#1
Alex M Ayoub, Laura M L Hawk, Ryan J Herzig, Jiewei Jiang, Andrea J Wisniewski, Clifford T Gee, Peiliang Zhao, Jin-Yi Zhu, Norbert Berndt, Nana K Offei-Addo, Thomas G Scott, Jun Qi, James E Bradner, Timothy R Ward, Ernst Schönbrunn, Gunda I Georg, William C K Pomerantz
Chemical inhibition of epigenetic regulatory proteins BrdT and Brd4 is emerging as a promising therapeutic strategy in contraception, cancer, and heart disease. We report an easily synthesized dihydropyridopyrmidine pan-BET inhibitor scaffold, which was uncovered via a virtual screen followed by testing in a fluorescence anisotropy assay. Dihydropyridpyimidine 3 was subjected to further characterization and is highly selective for the BET family of bromodomains. Structure-activity relationship data and ligand deconstruction highlight the importance of the substitution of the uracil moiety for potency and selectivity...
May 23, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28516956/selective-bet-bromodomain-inhibition-as-an-antifungal-therapeutic-strategy
#2
Flore Mietton, Elena Ferri, Morgane Champleboux, Ninon Zala, Danièle Maubon, Yingsheng Zhou, Mike Harbut, Didier Spittler, Cécile Garnaud, Marie Courçon, Murielle Chauvel, Christophe d'Enfert, Boris A Kashemirov, Mitchell Hull, Muriel Cornet, Charles E McKenna, Jérôme Govin, Carlo Petosa
Invasive fungal infections cause significant morbidity and mortality among immunocompromised individuals, posing an urgent need for new antifungal therapeutic strategies. Here we investigate a chromatin-interacting module, the bromodomain (BD) from the BET family of proteins, as a potential antifungal target in Candida albicans, a major human fungal pathogen. We show that the BET protein Bdf1 is essential in C. albicans and that mutations inactivating its two BDs result in a loss of viability in vitro and decreased virulence in mice...
May 18, 2017: Nature Communications
https://www.readbyqxmd.com/read/28515341/bet-bromodomain-inhibition-suppresses-innate-inflammatory-and-profibrotic-transcriptional-networks-in-heart-failure
#3
Qiming Duan, Sarah McMahon, Priti Anand, Hirsh Shah, Sean Thomas, Hazel T Salunga, Yu Huang, Rongli Zhang, Aarathi Sahadevan, Madeleine E Lemieux, Jonathan D Brown, Deepak Srivastava, James E Bradner, Timothy A McKinsey, Saptarsi M Haldar
Despite current standard of care, the average 5-year mortality after an initial diagnosis of heart failure (HF) is about 40%, reflecting an urgent need for new therapeutic approaches. Previous studies demonstrated that the epigenetic reader protein bromodomain-containing protein 4 (BRD4), an emerging therapeutic target in cancer, functions as a critical coactivator of pathologic gene transactivation during cardiomyocyte hypertrophy. However, the therapeutic relevance of these findings to human disease remained unknown...
May 17, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28504695/epigenetic-pathway-inhibitors-represent-potential-drugs-for-treating-pancreatic-and-bronchial-neuroendocrine-tumors
#4
K E Lines, M Stevenson, P Filippakopoulos, S Müller, H E Lockstone, B Wright, S Grozinsky-Glasberg, A B Grossman, S Knapp, D Buck, C Bountra, R V Thakker
Cancer is associated with alterations in epigenetic mechanisms such as histone modifications and methylation of DNA, and inhibitors targeting epigenetic mechanisms represent a novel class of anti-cancer drugs. Neuroendocrine tumors (NETs) of the pancreas (PNETs) and bronchus (BNETs), which may have 5-year survivals of <50% and as low as 5%, respectively, represent targets for such drugs, as >40% of PNETs and ~35% of BNETs have mutations of the multiple endocrine neoplasia type 1 (MEN1) gene, which encodes menin that modifies histones by interacting with histone methyltransferases...
May 15, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28499587/the-phosphodiesterase-4-inhibitor-apremilast-inhibits-th1-but-promotes-th17-responses-induced-by-6-sulfo-lacnac-slan-dendritic-cells
#5
Stephanie Oehrl, Hridayesh Prakash, Annette Ebling, Nina Trenkler, Priscila Wölbing, Anja Kunze, Thomas Döbel, Marc Schmitz, Alexander Enk, Knut Schäkel
BACKGROUND: The phosphodiesterase 4 (PDE4) inhibitor apremilast increases cellular cAMP levels and has proven effective in the treatment of psoriasis and psoriasis arthritis. We recently described 6-sulfo LacNAc dendritic cells (slanDCs) as immature DCs in blood and as a subset of inflammatory dermal DCs in psoriasis with a pronounced capacity to produce proinflammatory cytokines and to program Th17/Th1 T cell responses. OBJECTIVE: The aim of this study was to investigate possible immune regulatory effects of the PDE4 inhibitor apremilast on slanDCs...
April 20, 2017: Journal of Dermatological Science
https://www.readbyqxmd.com/read/28490401/immunopathologic-characteristics-of-nasal-polyps-in-adult-koreans-a-single-center-study
#6
Seung-Heon Shin, Yee-Hyuk Kim, Mi-Kyung Ye, Sung-Yong Choi
BACKGROUND: Chronic rhinosinusitis with nasal polyps (NP) (CRSwNP) is classified into eosinophilic and noneosinophilic types based on the level of tissue eosinophilia. The immunopathologic features of Western and Asian CRSwNP differ. OBJECTIVES: The aim of this study was to investigate the immunopathologic characteristics of Korean patients with eosinophilic NP versus noneosinophilic NP and those with atopic NP versus nonatopic NP. METHODS: Tissue samples were collected from 81 patients with NP and 24 controls...
May 1, 2017: American Journal of Rhinology & Allergy
https://www.readbyqxmd.com/read/28488390/mesenchymal-stem-cells-protect-from-acute-liver-injury-by-attenuating-hepatotoxicity-of-liver-nkt-cells-in-inos-and-ido-dependent-manner
#7
Marina Gazdic, Bojana Simovic Markovic, Ljubica Vucicevic, Tamara Nikolic, Valentin Djonov, Nebojsa Arsenijevic, Vladimir Trajkovic, Miodrag L Lukic, Vladislav Volarevic
The effects of mesenchymal stem cells (MSCs) on phenotype and function of natural killer T (NKT) cells, is not understood. We used concanavalin A (ConA) - and α-galactosylceramide (α-GalCer)-induced liver injury to evaluate effects of MSCs on NKT-dependent hepatotoxicity. Mouse MSCs (mMSCs) significantly reduced Con A- and α-GalCer-mediated hepatitis in C57Bl/6 mice, as demonstrated by histopathological and biochemical analysis, attenuated influx of inflammatory (T-bet(+) TNF-α, IFN-γ producing and GATA3(+) , IL-4-producing) liver NKT cells and down-regulated TNF-α, IFN-γ and IL-4 levels in the sera...
May 9, 2017: Journal of Tissue Engineering and Regenerative Medicine
https://www.readbyqxmd.com/read/28474499/inhibition-of-the-bet-family-of-epigenetic-reader-proteins-a-novel-principle-for-modulating-gene-expression-in-ige-activated-mast-cells
#8
Gianni Garcia-Faroldi, Elin Rönnberg, Mirjana Grujic, Gunnar Pejler
INTRODUCTION: The BET family of bromodomain-containing proteins constitute epigenetic readers that bind to acetylated lysine residues of core histones, thereby translating epigenetic histone marks to effects on gene expression. BET inhibitors are currently emerging as promising therapeutic agents for treatment of various pathological conditions. Here, we explored the potential of using BET inhibition to modulate IgE-mediated responses in mast cells. METHODS: We assessed the effects of BET inhibitors PFI-1, I-BET151, and I-BET762 on responses downstream of mast cell activation through IgE receptor cross-linking...
June 2017: Immunity, Inflammation and Disease
https://www.readbyqxmd.com/read/28468776/vulnerability-of-small-cell-lung-cancer-to-apoptosis-induced-by-the-combination-of-bet-bromodomain-proteins-and-bcl2-inhibitors
#9
Lloyd T Lam, Xiaoyu Lin, Emily J Faivre, Ziping Yang, Xiaoli Huang, Denise M Wilcox, Richard J Bellin, Sha Jin, Stephen K Tahir, Michael Mitten, Terry Magoc, Anahita Bhathena, Warren M Kati, Daniel H Albert, Yu Shen, Tamar Uziel
10% to 15% of all lung cancers are small cell lung cancer (SCLC). SCLC usually grows and metastasizes before it is diagnosed and relapses rapidly upon treatment. Unfortunately, no new targeted agent has been approved in the past 30 years for patients with SCLC. The BET (bromodomain and extra-terminal) proteins bind acetylated histones and recruit protein complexes to promote transcription initiation and elongation. BET proteins have been shown to regulate expression of key genes in oncogenesis such as MYC, CCND2, and BCL2L1 Here, we demonstrate that ~50% of SCLC cell lines are exquisitely sensitive to growth inhibition by the BET inhibitor, ABBV-075...
May 3, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28463487/structure-based-discovery-of-4-6-methoxy-2-methyl-4-quinolin-4-yl-9h-pyrimido-4-5-b-indol-7-yl-3-5-dimethylisoxazole-cd161-as-a-potent-and-orally-bioavailable-bet-bromodomain-inhibitor
#10
Yujun Zhao, Longchuan Bai, Liu Liu, Donna McEachern, Jeanne A Stuckey, Jennifer L Meagher, Chao-Yie Yang, Xu Ran, Bing Zhou, Yang Hu, Xiaoqin Li, Bo Wen, Ting Zhao, Siwei Li, Duxin Sun, Shaomeng Wang
We have designed and synthesized 9H-pyrimido[4,5-b]indole-containing compounds to obtain potent and orally bioavailable BET inhibitors. By incorporation of an indole or a quinoline moiety to the 9H-pyrimido[4,5-b]indole core, we identified a series of small molecules showing high binding affinities to BET proteins and low nanomolar potencies in inhibition of cell growth in acute leukemia cell lines. One such compound, 4-(6-methoxy-2-methyl-4-(quinolin-4-yl)-9H-pyrimido[4,5-b]indol-7-yl)-3,5-dimethylisoxazole (31) has excellent microsomal stability and good oral pharmacokinetics in rats and mice...
May 11, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28455436/egr2-and-3-inhibit-t-bet-mediated-ifn-%C3%AE-production-in-t-cells
#11
Randeep Singh, Tizong Miao, Alistair L J Symonds, Becky Omodho, Suling Li, Ping Wang
T-bet is important for differentiation of cytotoxic CD8 and Th1 CD4 T cells. We have discovered that Egr2 and 3 are potent inhibitors of T-bet function in CD4 and CD8 effector T cells. Egr2 and 3 were essential to suppress Th1 differentiation in Th2 and Th17 conditions in vitro and also to control IFN-γ-producing CD4 and CD8 T cells in response to virus infection. Together with Egr2 and 3, T-bet is induced in naive T cells by Ag stimulation, but Egr2 and 3 expression was inhibited by Th1-inducing cytokines...
June 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28426098/targeting-chromatin-defects-in-selected-solid-tumors-based-on-oncogene-addiction-synthetic-lethality-and-epigenetic-antagonism
#12
D Morel, G Almouzni, J-C Soria, S Postel-Vinay
Background: Although the role of epigenetic abnormalities has been studied for several years in cancer genesis and development, epigenetic-targeting drugs have historically failed to demonstrate efficacy in solid malignancies. However, successful targeting of chromatin remodeling deficiencies, histone writers and histone reader alterations has been achieved very recently using biomarker-driven and mechanism-based approaches. Epigenetic targeting is now one of the most active areas in drug development and could represent novel therapeutic opportunity for up to 25% of all solid tumors...
February 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28424242/mtorc1-promotes-t-bet-phosphorylation-to-regulate-th1-differentiation
#13
Olesya Chornoguz, Robert S Hagan, Azeb Haile, Matthew L Arwood, Christopher J Gamper, Arnob Banerjee, Jonathan D Powell
CD4(+) T cells lacking the mTORC1 activator Rheb fail to secrete IFN-γ under Th1 polarizing conditions. We hypothesized that this phenotype is due to defects in regulation of the canonical Th1 transcription factor T-bet at the level of protein phosphorylation downstream of mTORC1. To test this hypothesis, we employed targeted mass-spectrometry proteomic analysis-multiple reaction monitoring mass spectrometry. We used this method to detect and quantify predicted phosphopeptides derived from T-bet. By analyzing activated murine wild-type and Rheb-deficient CD4(+) T cells, as well as murine CD4(+) T cells activated in the presence of rapamycin, a pharmacologic inhibitor of mTORC1, we were able to identify six T-bet phosphorylation sites...
May 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28423651/succinate-dehydrogenase-b-deficient-cancer-cells-are-highly-sensitive-to-bromodomain-and-extra-terminal-inhibitors
#14
Satoshi Kitazawa, Shunsuke Ebara, Ayumi Ando, Yuji Baba, Yoshinori Satomi, Tomoyoshi Soga, Takahito Hara
Mutations in succinate dehydrogenase B (SDHB) gene are frequently observed in several tumors and associated with poor prognosis in these tumors. Therefore, drugs effective for SDHB-deficient tumors could fulfill an unmet medical need. In addition, such drugs would have an advantage in that selection of patients with SDHB-mutant cancer could increase the probability of success in clinical trials. Currently, however, the characteristics of SDHB-deficient cancers are not completely understood. Here, we established SDHB knockout cancer cell lines from human colon cancer HCT116 cells using the clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 knockout system, and clarified its metabolic characteristics...
April 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423491/the-mir-25-93-106b-cluster-regulates-tumor-metastasis-and-immune-evasion-via-modulation-of-cxcl12-and-pd-l1
#15
Michele Cioffi, Sara M Trabulo, Mireia Vallespinos, Deepak Raj, Tony Bou Kheir, Meng-Lay Lin, Julfa Begum, Ann-Marie Baker, Ala Amgheib, Jaimy Saif, Manuel Perez, Joaquim Soriano, Manuel Desco, Maria Victoria Gomez-Gaviro, Lorena Cusso, Diego Megias, Alexandra Aicher, Christopher Heeschen
The stromal microenvironment controls response to injury and inflammation, and is also an important determinant of cancer cell behavior. However, our understanding of its modulation by miRNA (miR) and their respective targets is still sparse. Here, we identified the miR-25-93-106b cluster and two new target genes as critical drivers for metastasis and immune evasion of cancer cells. Using miR-25-93-106b knockout mice or antagomiRs, we demonstrated regulation of the production of the chemoattractant CXCL12 controlling bone marrow metastasis...
March 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423226/rvx-208-a-novel-bet-protein-inhibitor-role-as-an-inducer-of-apo-a-i-hdl-and-beyond
#16
Gopal C Ghosh, Rajarshi Bhadra, Raktim K Ghosh, Kinjal Banerjee, Anjan Gupta
Low density cholesterol (LDL) has been the prime target of currently available lipid-lowering therapies although current research is expanding the focus beyond LDL lowering and has included high density cholesterol (HDL) also as the target. Bromo and extra-terminal (BET) proteins are implicated in the regulation of transcription of several regulatory genes and regulation of pro-inflammatory pathways. As atherosclerosis is an inflammatory pathway and studies showed that BET inhibition has a role in inhibiting inflammation, the concept of BET inhibition came in the field of atherosclerosis...
April 19, 2017: Cardiovascular Therapeutics
https://www.readbyqxmd.com/read/28420416/emerging-therapies-for-acute-myeloid-leukemia
#17
REVIEW
Caner Saygin, Hetty E Carraway
Acute myeloid leukemia (AML) is characterized by clinical and biological heterogeneity. Despite the advances in our understanding of its pathobiology, the chemotherapy-directed management has remained largely unchanged in the past 40 years. However, various novel agents have demonstrated clinical activity, either as single agents (e.g., isocitrate dehydrogenase (IDH) inhibitors, vadastuximab) or in combination with standard induction/consolidation at diagnosis and with salvage regimens at relapse. The classes of agents described in this review include novel cytotoxic chemotherapies (CPX-351 and vosaroxin), epigenetic modifiers (guadecitabine, IDH inhibitors, histone deacetylase (HDAC) inhibitors, bromodomain and extraterminal (BET) inhibitors), FMS-like tyrosine kinase receptor 3 (FLT3) inhibitors, and antibody-drug conjugates (vadastuximab), as well as cell cycle inhibitors (volasertib), B-cell lymphoma 2 (BCL-2) inhibitors, and aminopeptidase inhibitors...
April 18, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28418907/bh3-mimetics-and-bet-inhibitors-elicit-enhanced-lethality-in-malignant-glioma
#18
Chiaki Tsuge Ishida, Elena Bianchetti, Chang Shu, Marc-Eric Halatsch, M Andrew Westhoff, Georg Karpel-Massler, Markus D Siegelin
Drug combination therapies remain pivotal for the treatment of heterogeneous malignancies, such as glioblastomas. Here, we show a novel lethal interaction between Bcl-xL and c-myc inhibition accomplished by bromodomain protein inhibitors. Established, patient-derived xenograft and stem cell-like glioma cells were treated with the novel bromodomain protein inhibitors, JQ1 and OTX015, along with BH3-mimetics, ABT263 or Obatoclax. Synergy was assessed by calculation of CI values. Small interfering RNAs (siRNAs) were used for gene silencing and mechanistic studies...
May 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28416490/preclinical-characterization-of-bet-family-bromodomain-inhibitor-abbv-075-suggests-combination-therapeutic-strategies
#19
Mai H Bui, Xiaoyu Lin, Daniel H Albert, Leiming Li, Lloyd T Lam, Emily J Faivre, Scott Warder, Xiaoli Huang, Denise Wilcox, Cherrie K Donawho, George S Sheppard, Le Wang, Steve Fidanze, John K Pratt, Dachun Liu, Lisa Hasvold, Tamar Uziel, Xin Lu, Fred Kohlhapp, Guowei Fang, Steven W Elmore, Saul H Rosenberg, Keith F McDaniel, Warren M Kati, Yu Shen
ABBV-075 is a potent and selective BET family bromodomain inhibitor that recently entered Phase I clinical trials. Comprehensive preclinical characterization of ABBV-075 demonstrated broad activity across cell lines and tumor models representing a variety of hematological malignancies and solid tumor indications. In most cancer cell lines derived from solid tumors, ABBV-075 triggers prominent G1 cell cycle arrest without extensive apoptosis. In this study, we show that ABBV-075 efficiently triggers apoptosis in acute myeloid leukemia (AML), non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM) cells...
April 17, 2017: Cancer Research
https://www.readbyqxmd.com/read/28415755/mitochondrial-matrix-chaperone-and-c-myc-inhibition-causes-enhanced-lethality-in-glioblastoma
#20
Chiaki Tsuge Ishida, Chang Shu, Marc-Eric Halatsch, Mike-Andrew Westhoff, Dario C Altieri, Georg Karpel-Massler, Markus David Siegelin
Malignant gliomas display high levels of the transcription factor c-myc and organize a tumor specific chaperone network within mitochondria. Here, we show that c-myc along with mitochondrial chaperone inhibition displays massive tumor cell death. Inhibition of mitochondrial matrix chaperones and c-myc was established by utilizing genetic as well as pharmacological approaches. Bromodomain and extraterminal (BET) family protein inhibitors, JQ1 and OTX015, were used for c-myc inhibition. Gamitrinib was applied to interfere with mitochondrial matrix chaperones...
March 15, 2017: Oncotarget
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