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BRD2 OR BRD3 OR BRD4 OR JQ1

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https://www.readbyqxmd.com/read/29773735/brd4-and-myc-clarifying-regulatory-specificity
#1
Arianna Sabò, Bruno Amati
No abstract text is available yet for this article.
May 18, 2018: Science
https://www.readbyqxmd.com/read/29767555/protective-effect-of-the-bet-protein-inhibitor-jq1-in-cisplatin-induced-nephrotoxicity
#2
Liping Sun, Jing Liu, Yanggang Yuan, Xinzhou Zhang, Zheng Dong
As a potent chemotherapy drug, cisplatin is also notorious for its side effects including nephrotoxicity in kidneys, presenting a pressing need to identify renoprotective agents. Cisplatin nephrotoxicity involves epigenetic regulations, including changes in histone acetylation. Bromodomain and extra-terminal (BET) proteins are "readers" of the epigenetic code of histone acetylation. Here, we investigated the potential renoprotective effects of JQ1, a small molecule inhibitor of BET proteins. We show that JQ1 significantly ameliorated cisplatin-induced nephrotoxicity in mice as indicated by the measurements of kidney function, histopathology, and renal tubular apoptosis...
May 16, 2018: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/29764999/targetable-bet-proteins-and-e2f1-dependent-transcriptional-program-maintains-the-malignancy-of-glioblastoma
#3
Liang Xu, Ye Chen, Anand Mayakonda, Lynnette Koh, Yuk Kien Chong, Dennis L Buckley, Edwin Sandanaraj, See Wee Lim, Ruby Yu-Tong Lin, Xin-Yu Ke, Mo-Li Huang, Jianxiang Chen, Wendi Sun, Ling-Zhi Wang, Boon Cher Goh, Huy Q Dinh, Dennis Kappei, Georg E Winter, Ling-Wen Ding, Beng Ti Ang, Benjamin P Berman, James E Bradner, Carol Tang, H Phillip Koeffler
Competitive BET bromodomain inhibitors (BBIs) targeting BET proteins (BRD2, BRD3, BRD4, and BRDT) show promising preclinical activities against brain cancers. However, the BET protein-dependent glioblastoma (GBM)-promoting transcriptional network remains elusive. Here, with mechanistic exploration of a next-generation chemical degrader of BET proteins (dBET6), we reveal a profound and consistent impact of BET proteins on E2F1- dependent transcriptional program in both differentiated GBM cells and brain tumor-initiating cells...
May 15, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29764756/straightforward-hit-identification-approach-in-fragment-based-discovery-of-bromodomain-containing-protein-4-brd4-inhibitors
#4
Petro Borysko, Yurii S Moroz, Oleksandr V Vasylchenko, Vasyl V Hurmach, Anastasia Starodubtseva, Natalia Stefanishena, Kateryna Nesteruk, Sergey Zozulya, Ivan S Kondratov, Oleksandr O Grygorenko
A combination approach of a fragment screening and "SAR by catalog" was used for the discovery of bromodomain-containing protein 4 (BRD4) inhibitors. Initial screening of 3695-fragment library against bromodomain 1 of BRD4 using thermal shift assay (TSA), followed by initial hit validation, resulted in 73 fragment hits, which were used to construct a follow-up library selected from available screening collection. Additionally, analogs of inactive fragments, as well as a set of randomly selected compounds were also prepared (3 × 3200 compounds in total)...
May 9, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29760405/arid1a-mutation-sensitizes-most-ovarian-clear-cell-carcinomas-to-bet-inhibitors
#5
Katrien Berns, Joseph J Caumanns, E Marielle Hijmans, Annemiek M C Gennissen, Tesa M Severson, Bastiaan Evers, G Bea A Wisman, Gert Jan Meersma, Cor Lieftink, Roderick L Beijersbergen, Hiroaki Itamochi, Ate G J van der Zee, Steven de Jong, René Bernards
Current treatment for advanced stage ovarian clear cell cancer is severely hampered by a lack of effective systemic therapy options, leading to a poor outlook for these patients. Sequencing studies revealed that ARID1A is mutated in over 50% of ovarian clear cell carcinomas. To search for a rational approach to target ovarian clear cell cancers with ARID1A mutations, we performed kinome-centered lethality screens in a large panel of ovarian clear cell carcinoma cell lines. Using the largest OCCC cell line panel established to date, we show here that BRD2 inhibition is predominantly lethal in ARID1A mutated ovarian clear cell cancer cells...
May 15, 2018: Oncogene
https://www.readbyqxmd.com/read/29760044/nk-cells-mediate-synergistic-antitumor-effects-of-combined-inhibition-of-hdac6-and-bet-in-a-sclc-preclinical-model
#6
Yan Liu, Yuyang Li, Shengwu Liu, Dennis O Adeegbe, Camilla L Christensen, Max M Quinn, Ruben Dries, Shiwei Han, Kevin Buczkowski, Xiaoen Wang, Ting Chen, Peng Gao, Hua Zhang, Fei Li, Peter S Hammerman, James E Bradner, Steven N Quayle, Kwok-Kin Wong
Small cell lung cancer (SCLC) has the highest malignancy among all lung cancers, exhibiting aggressive growth and early metastasis to distant sites. For 30 years, treatment options for SCLC have been limited to chemotherapy, warranting the need for more effective treatments. Frequent inactivation of TP53 and RB1 as well as histone dysmodifications in SCLC suggest that transcriptional and epigenetic regulations play a major role in SCLC disease evolution. Here we performed a synthetic lethal screen using the BET inhibitor JQ1 and an shRNA library targeting 550 epigenetic genes in treatment-refractory SCLC xenograft models and identified HDAC6 as a synthetic lethal target in combination with JQ1...
May 14, 2018: Cancer Research
https://www.readbyqxmd.com/read/29759937/identification-of-epigenetic-regulators-of-dux4-fl-for-targeted-therapy-of-facioscapulohumeral-muscular-dystrophy
#7
Charis L Himeda, Takako I Jones, Ching-Man Virbasius, Lihua Julie Zhu, Michael R Green, Peter L Jones
Facioscapulohumeral muscular dystrophy (FSHD) is caused by epigenetic de-repression of the disease locus, leading to pathogenic misexpression of the DUX4 gene in skeletal muscle. While the factors and pathways involved in normal repression of the FSHD locus in healthy cells have been well characterized, very little is known about those responsible for the aberrant activation of DUX4-fl in FSHD myocytes. Reasoning that DUX4-fl activators might represent useful targets for small molecule inhibition, we performed a highly targeted, candidate-based screen of epigenetic regulators in primary FSHD myocytes...
April 26, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29758518/benzoxazinone-containing-3-5-dimethylisoxazole-derivatives-as-bet-bromodomain-inhibitors-for-treatment-of-castration-resistant-prostate-cancer
#8
Xiaoqian Xue, Yan Zhang, Chao Wang, Maofeng Zhang, Qiuping Xiang, Junjian Wang, Anhui Wang, Chenchang Li, Cheng Zhang, Lingjiao Zou, Rui Wang, Shuang Wu, Yongzhi Lu, Hongwu Chen, Ke Ding, Guohui Li, Yong Xu
The bromodomain and extra-terminal proteins (BET) have emerged as promising therapeutic targets for the treatment of castration-resistant prostate cancer (CRPC). We report the design, synthesis and evaluation of a new series of benzoxazinone-containing 3,5-dimethylisoxazole derivatives as selective BET inhibitors. One of the new compounds, (R)-12 (Y02234), binds to BRD4(1) with a Kd value of 110 nM and blocks bromodomain and acetyl lysine interactions with an IC50 value of 100 nM. It also exhibits selectivity for BET over non-BET bromodomain proteins and demonstrates reasonable anti-proliferation and colony formation inhibition effect in prostate cancer cell lines such as 22Rv1 and C4-2B...
April 21, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29755274/nut-carcinoma-of-the-sinonasal-tract-infiltrating-the-orbit-in-a-man-with-birdshot-chorioretinitis
#9
Wesley Chan, Martin J Bullock, Arif F Samad, Curtis W Archibald, J Godfrey Heathcote
A 48-year-old man with a history of birdshot chorioretinitis presented with blurry vision, retro-bulbar pain and sinusitis. Though visual acuity was unaffected, he had left optic disc oedema and mild restriction of left eye abduction. His symptoms progressed quickly, with diplopia in primary gaze, epistaxis from his left nostril, and a left relative afferent pupillary defect (RAPD). On computed tomography, there was a mass in the nasal cavity that extended through the left cribriform plate and lamina papyracea and posteriorly into the optic canal...
January 2018: Saudi Journal of Ophthalmology: Official Journal of the Saudi Ophthalmological Society
https://www.readbyqxmd.com/read/29751762/hiv-latency-reversing-agents-act-through-tat-post-translational-modifications
#10
Georges Khoury, Talia M Mota, Shuang Li, Carolin Tumpach, Michelle Y Lee, Jonathan Jacobson, Leigh Harty, Jenny L Anderson, Sharon R Lewin, Damian F J Purcell
BACKGROUND: Different classes of latency reversing agents (LRAs) are being evaluated to measure their effects in reactivating HIV replication from latently infected cells. A limited number of studies have demonstrated additive effects of LRAs with the viral protein Tat in initiating transcription, but less is known about how LRAs interact with Tat, particularly through basic residues that may be post-translationally modified to alter the behaviour of Tat for processive transcription and co-transcriptional RNA processing...
May 11, 2018: Retrovirology
https://www.readbyqxmd.com/read/29748248/bromodomain-protein-brd4-is-increased-in-human-placentas-from-women-with-early-onset-preeclampsia
#11
Stella Liong, Gillian Barker, Martha Lappas
Preeclampsia affects 5% of all pregnancies and is a serious disorder of pregnancy, characterised by high maternal blood pressure, placental hypoxia, fluid retention (oedema) and proteinuria. Women with preeclampsia are associated with exaggerated levels of pro-inflammatory cytokines, chemokines and anti-angiogenic factors such as soluble fms-like tyrosine kinase-1 (sFLT1). Studies in non-gestational tissues have described the bromodomain (BRD) and extraterminal family of proteins, in particular BRD4 to play a critical role in propagating inflammation and is currently a therapeutic target for treating cancer, lung inflammation and asthma...
June 2018: Reproduction: the Official Journal of the Society for the Study of Fertility
https://www.readbyqxmd.com/read/29748211/anti-leukemic-efficacy-of-bet-inhibitor-in-a-preclinical-mouse-model-of-mll-af4-infant-all
#12
Michela Bardini, Luca Trentin, Francesca Rizzo, Margherita Vieri, Angela M Savino, Patricia Garrido Castro, Grazia Fazio, Eddy H J Van Roon, Mark Kerstjens, Nicholas N Smithers, Rab K Prinjha, Geertruy Te Kronnie, Giuseppe Basso, Ronald W Stam, Rob Pieters, Andrea Biondi, Giovanni Cazzaniga
MLL-rearranged acute lymphoblastic leukemia occurring in infants is a rare but very aggressive leukemia, typically associated with a dismal prognosis. Despite the development of specific therapeutic protocols, infant patients with MLL-rearranged ALL still suffer from a low cure rate. At present, novel therapeutic approaches are urgently needed. Recently, the use of small molecule inhibitors targeting the epigenetic regulators of the MLL complex emerged as a promising strategy for the development of a targeted therapy...
May 10, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29743242/cyclin-dependent-kinase-7-cdk7-mediated-phosphorylation-of-the-cdk9-activation-loop-promotes-p-tefb-assembly-with-tat-and-proviral-hiv-reactivation
#13
Uri Mbonye, Benlian Wang, Giridharan Gokulrangan, Wuxian Shi, Sichun Yang, Jonathan Karn
The HIV trans-activator Tat recruits the host transcription elongation factor P-TEFb to stimulate proviral transcription. Phosphorylation of Thr186 on the activation loop (T-loop) of cyclin-dependent kinase 9 (CDK9) is essential for its kinase activity and assembly of CDK9 and cyclin T1 (CycT1) to form functional P-TEFb. Phosphorylation of a second highly conserved T-loop site, Ser175, alters the competitive binding of Tat and the host recruitment factor bromodomain containing 4 (BRD4) to P-TEFb. Here, we investigated the intracellular mechanisms that regulate these key phosphorylation events required for HIV transcription...
May 9, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29732121/optimization-of-a-bump-and-hole-approach-to-allele-selective-bet-bromodomain-inhibition
#14
A C Runcie, M Zengerle, K-H Chan, A Testa, L van Beurden, M G J Baud, O Epemolu, L C J Ellis, K D Read, V Coulthard, A Brien, A Ciulli
Allele-specific chemical genetics enables selective inhibition within families of highly-conserved proteins. The four BET (bromodomain & extra-terminal domain) proteins - BRD2, BRD3, BRD4 and BRDT bind acetylated chromatin via their bromodomains and regulate processes such as cell proliferation and inflammation. BET bromodomains are of particular interest, as they are attractive therapeutic targets but existing inhibitors are pan-selective. We previously established a bump-&-hole system for the BET bromodomains, pairing a leucine/alanine mutation with an ethyl-derived analogue of an established benzodiazepine scaffold...
March 7, 2018: Chemical Science
https://www.readbyqxmd.com/read/29730189/design-synthesis-and-biological-evaluation-of-benzo-cd-indol-2-1h-ones-derivatives-as-brd4-inhibitors
#15
Yuxin Feng, Senhao Xiao, Yantao Chen, Hao Jiang, Na Liu, Cheng Luo, Shijie Chen, Hua Chen
Compound 1 bearing with benzo [cd]indol-2(1H)-one scaffold was identified as an effective BRD4 inhibitor through the AlphaScreen-based high-throughput screening and its high-resolution crystal structure with BRD4_BD1 protein. A series of 48 compounds were designed and synthesized by structural optimization on compound 1. All the compounds have been evaluated for their BRD4 inhibitory activities. The results showed that compounds 23, 24, 28 and 44 are the most potential ones with the IC50 values of 1.02 μM, 1...
April 28, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29724031/targeting-general-transcriptional-machinery-as-a-therapeutic-strategy-for-adult-t-cell-leukemia
#16
REVIEW
Regina Wan Ju Wong, Takashi Ishida, Takaomi Sanda
Cancer cells are highly reliant on certain molecular pathways, which support their survival and proliferation. The fundamental concept of molecularly targeted therapy is to target a protein that is specifically deregulated or overexpressed in cancer cells. However, drug resistance and tumor heterogeneity are major obstacles in the development of specific inhibitors. Additionally, many driver oncogenes exert their oncogenic property via abnormal expression without having genetic mutations. Interestingly, recent accumulating evidence has demonstrated that many critical cancer genes are driven by a unique class of enhancers termed super-enhancers...
May 2, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29717765/bromodomain%C3%A2-containing-protein-4-is-critical-for-the-antiproliferative-and-pro%C3%A2-apoptotic-effects-of-gambogic-acid-in-anaplastic-thyroid-cancer
#17
Yonghui Wang, Wei Wang, Hongqin Sun
Gambogic acid (GA) has been widely used as an anticancer drug for different tumors, including thyroid cancer. However, the potential function and molecular mechanisms of GA in anaplastic thyroid cancer (ATC) has not been illustrated thus far. The aim of the present study was to demonstrate the antitumor effects of GA on ATC cells and investigate its underlying molecular mechanisms. The results revealed that GA significantly decreased the viability and proliferation, as well as induced cell apoptosis in ATC cell lines...
April 26, 2018: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29716963/plk1-inhibition-enhances-the-efficacy-of-bet-epigenetic-reader-blockade-in-castration-resistant-prostate-cancer
#18
Fengyi Mao, Jie Li, Qian Luo, Ruixin Wang, Yifan Kong, Colin Carlock, Zian Liu, Bennett D Elzey, Xiaoqi Liu
Polo-like kinase 1 (Plk1), a crucial regulator of cell cycle progression, is overexpressed in multiple types of cancers, and has been proven to be a potent and promising target for cancer treatment. In case of prostate cancer, we once showed that anti-neoplastic activity of Plk1 inhibitor is largely due to inhibition of androgen receptor (AR) signaling. However, we also discovered that Plk1 inhibition causes activation of the β-catenin pathway and increased ex-pression of c-Myc, eventually resulting in resistance to Plk1 inhibition...
May 1, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29709701/co-targeting-of-bet-proteins-and-hdacs-as-a-novel-approach-to-trigger-apoptosis-in-rhabdomyosarcoma-cells
#19
Julius C Enßle, Cathinka Boedicker, Marek Wanior, Meike Vogler, Stefan Knapp, Simone Fulda
Histone acetylation marks exert essential functions in regulating gene expression. These marks are written by histone acetyltransferases (HATs), removed by histone deacetylases (HDACs) and read by e.g. BET proteins. While BET inhibitors are promising new anticancer drugs, little is yet known on their antitumor activity in rhabdomyosarcoma (RMS). We therefore investigated the efficacy of the prototypic BET inhibitor JQ1 alone or in combination with other epigenetic modifiers, namely HDAC inhibitors (HDACIs)...
April 27, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29703820/insulin-like-growth-factor-2-mrna-binding-protein-3-is-a-novel-post-transcriptional-regulator-of-ewing-sarcoma-malignancy
#20
Caterina Mancarella, Michela Pasello, Selena Ventura, Andrea Grilli, Linda Calzolari, Lisa Toracchio, Pier Luigi Lollini, Davide Maria Donati, Piero Picci, Stefano Ferrari, Katia Scotlandi
PURPOSE: Large-scale sequencing studies have indicated that besides genomic alterations, the post-transcriptional regulation of gene expression or epigenetic mechanisms largely influences the clinical behavior of Ewing sarcoma (ES). We investigated the significance of the RNA-binding protein IGF2BP3 in the regulation of ES aggressiveness. EXPERIMENTAL DESIGN:  Explorative study was performed in 15 patients with localized ES using RNAseq. Next, 128 patients with localized ES were divided into two cohorts...
April 27, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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