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Cancer AND BRD4

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https://www.readbyqxmd.com/read/29777912/a-super-enhancer-maintains-homeostatic-expression-of-regnase-1
#1
Riyun Yang, Yuanyuan Wu, Yue Ming, Yuanpei Xu, Shouyan Wang, Jianbo Shen, Chenlu Wang, Xia Chen, Yongming Wang, Renfang Mao, Yihui Fan
Regnase-1 is not only a key component in maintaining intracellular homeostasis but also a critical negative regulator in preventing autoimmune diseases and cancer development. To keep homeostatic state, Regnase-1 has to be maintained at a desired level in multiple cell types. However, the molecular mechanism of keeping a certain transcriptional level of Reganase-1 is largely unknown. In this study, we found a super-enhancer (Reg-1-SE) around Regnase-1 gene is able to control the homeostatic expression of Regnase-1...
May 16, 2018: Gene
https://www.readbyqxmd.com/read/29776834/bet-bromodomain-ligands-probing-the-wpf-shelf-to-improve-brd4-bromodomain-affinity-and-metabolic-stability
#2
Laura E Jennings, Matthias Schiedel, David S Hewings, Sarah Picaud, Corentine M C Laurin, Paul A Bruno, Joseph P Bluck, Amy R Scorah, Larissa See, Jessica K Reynolds, Mustafa Moroglu, Ishna N Mistry, Amy Hicks, Pavel Guzanov, James Clayton, Charles N G Evans, Giulia Stazi, Philip C Biggin, Anna K Mapp, Ester M Hammond, Philip G Humphreys, Panagis Filippakopoulos, Stuart J Conway
Ligands for the bromodomain and extra-terminal domain (BET) family of bromodomains have shown promise as useful therapeutic agents for treating a range of cancers and inflammation. Here we report that our previously developed 3,5-dimethylisoxazole-based BET bromodomain ligand (OXFBD02) inhibits interactions of BRD4(1) with the RelA subunit of NF-κB, in addition to histone H4. This ligand shows a promising profile in a screen of the NCI-60 panel but was rapidly metabolised (t½  = 39.8 min). Structure-guided optimisation of compound properties led to the development of the 3-pyridyl-derived OXFBD04...
May 15, 2018: Bioorganic & Medicinal Chemistry
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/29758518/benzoxazinone-containing-3-5-dimethylisoxazole-derivatives-as-bet-bromodomain-inhibitors-for-treatment-of-castration-resistant-prostate-cancer
#4
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/29748248/bromodomain-protein-brd4-is-increased-in-human-placentas-from-women-with-early-onset-preeclampsia
#5
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/29730189/design-synthesis-and-biological-evaluation-of-benzo-cd-indol-2-1h-ones-derivatives-as-brd4-inhibitors
#6
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
#7
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
#8
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
#9
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/29670088/a-cancer-vaccine-mediated-postoperative-immunotherapy-for-recurrent-and-metastatic-tumors
#10
Tingting Wang, Dangge Wang, Haijun Yu, Bing Feng, Fangyuan Zhou, Hanwu Zhang, Lei Zhou, Shi Jiao, Yaping Li
Vaccines to induce effective and sustained antitumor immunity have great potential for postoperative cancer therapy. However, a robust cancer vaccine simultaneously eliciting tumor-specific immunity and abolishing immune resistance continues to be a challenge. Here we present a personalized cancer vaccine (PVAX) for postsurgical immunotherapy. PVAX is developed by encapsulating JQ1 (a BRD4 inhibitor) and indocyanine green (ICG) co-loaded tumor cells with a hydrogel matrix. Activation of PVAX by 808 nm NIR laser irradiation significantly inhibits the tumor relapse by promoting the maturation of dendritic cells and eliciting tumor infiltration of cytotoxic T lymphocytes...
April 18, 2018: Nature Communications
https://www.readbyqxmd.com/read/29656650/discovery-of-tetrahydroquinoxalines-as-bromodomain-and-extra-terminal-domain-bet-inhibitors-with-selectivity-for-the-second-bromodomain
#11
Robert P Law, Stephen J Atkinson, Paul Bamborough, Chun-Wa Chung, Emmanuel H Demont, Laurie J Gordon, Matthew Lindon, Rab K Prinjha, Allan J B Watson, David Jonathan Hirst
The bromodomain and extra-terminal domain (BET) family of proteins bind acetylated lysine residues on histone proteins. The four BET bromodomains, BRD2, BRD3, BRD4 and BRDT, each contain two bromodomain modules. BET bromodomain inhibition is a potential therapy for various cancers and immunoinflammatory diseases, but few reported inhibitors show selectivity within the BET family. Inhibitors with selectivity for the first or second bromodomain are desired to aid investigation of the biological function of these domains...
April 15, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29642362/re-prostate-cancer-associated-spop-mutations-confer-resistance-to-bet-inhibitors-through-stabilization-of-brd4
#12
Anthony Atala
No abstract text is available yet for this article.
April 2018: Journal of Urology
https://www.readbyqxmd.com/read/29629903/zmynd8-acetylation-mediates-hif-dependent-breast-cancer-progression-and-metastasis
#13
Yan Chen, Bo Zhang, Lei Bao, Lai Jin, Mingming Yang, Yan Peng, Ashwani Kumar, Jennifer E Wang, Chenliang Wang, Xuan Zou, Chao Xing, Yingfei Wang, Weibo Luo
Altered epigenetic reprogramming contributes to breast cancer progression and metastasis. How the epigenetic reader mediates breast cancer progression remains poorly understood. Here, we showed that the epigenetic reader zinc finger MYND-type containing 8 (ZMYND8) is induced by HIF-1 and HIF-2 in breast cancer cells and also upregulated in human breast tumors, and is correlated with poor survival of patients with breast cancer. Genetic deletion of ZMYND8 decreases breast cancer cell colony formation, migration, and invasion in vitro, and inhibits breast tumor growth and metastasis to the lungs in mice...
April 9, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29622725/slam-seq-defines-direct-gene-regulatory-functions-of-the-brd4-myc-axis
#14
Matthias Muhar, Anja Ebert, Tobias Neumann, Christian Umkehrer, Julian Jude, Corinna Wieshofer, Philipp Rescheneder, Jesse J Lipp, Veronika A Herzog, Brian Reichholf, David A Cisneros, Thomas Hoffmann, Moritz F Schlapansky, Pooja Bhat, Arndt von Haeseler, Thomas Köcher, Anna C Obenauf, Johannes Popow, Stefan L Ameres, Johannes Zuber
Defining direct targets of transcription factors and regulatory pathways is key to understanding their roles in physiology and disease. Here we combine SLAM-seq, a method for direct quantification of newly synthesized mRNAs, with pharmacological and chemical-genetic perturbation to define regulatory functions of two transcriptional hubs in cancer, BRD4 and MYC, and to interrogate direct responses to BET bromodomain inhibitors (BETi). We find that BRD4 acts as general co-activator of RNA polymerase II (Pol2)-dependent transcription, which is broadly repressed upon high-dose BETi treatment...
April 5, 2018: Science
https://www.readbyqxmd.com/read/29603290/bet-ting-on-nrf2-how-nrf2-signaling-can-influence-the-therapeutic-activities-of-bet-protein-inhibitors
#15
REVIEW
Nirmalya Chatterjee, Dirk Bohmann
BET proteins such as Brd3 and Brd4 are chromatin-associated factors, which control gene expression programs that promote inflammation and cancer. The Nrf2 transcription factor is a master regulator of genes that protect the organism against xenobiotic attack and oxidative stress. Nrf2 has demonstrated anti-inflammatory activity and can support cancer cell malignancy. This review describes the discovery, mechanism and biomedical implications of the regulatory interplay between Nrf2 and BET proteins. Both Nrf2 and BET proteins are established drug targets...
March 30, 2018: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
https://www.readbyqxmd.com/read/29596834/azd5153-a-novel-brd4-inhibitor-suppresses-human-thyroid-carcinoma-cell-growth-in-vitro-and-in-vivo
#16
Kun Xu, Dexuan Chen, Dong Qian, Shihu Zhang, Yi Zhang, Song Guo, Zhaoqun Ma, Shui Wang
The development of novel anti-papillary thyroid carcinoma agents is urgent. AZD5153 is a novel and specific Bromodomain-containing protein 4 (BRD4) inhibitor. Here, we show that AZD5153 dose-dependently inhibited survival, proliferation and cell cycle progression in TPC-1 cells and primary human thyroid carcinoma cells. Yet, it was non-cytotoxic to the primary thyroid epithelial cells. AZD5153 induced caspase-3/-9 and apoptosis activation in TPC-1 cells and primary cancer cells. Its cytotoxicity in TPC-1 cells was significantly attenuated with co-treatment of the caspase inhibitors...
March 30, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29581547/protein-targeting-chimeric-molecules-specific-for-bromodomain-and-extra-terminal-motif-family-proteins-are-active-against-pre-clinical-models-of-multiple-myeloma
#17
Xiaohui Zhang, Hans C Lee, Fazal Shirazi, Veerabhadran Baladandayuthapani, Heather Lin, Isere Kuiatse, Hua Wang, Richard J Jones, Zuzana Berkova, Ram Kumar Singh, Jing Lu, Yimin Qian, Kanak Raina, Kevin G Coleman, Craig M Crews, Bingzong Li, Huihan Wang, Yared Hailemichael, Sheeba K Thomas, Zhiqiang Wang, R Eric Davis, Robert Z Orlowski
Bromodomain and extraterminal (BET) domain containing protein (BRD)-4 modulates the expression of oncogenes such as c-myc, and is a promising therapeutic target in diverse cancer types. We performed pre-clinical studies in myeloma models with bi-functional protein-targeting chimeric molecules (PROTACs) which target BRD4 and other BET family members for ubiquitination and proteasomal degradation. PROTACs potently reduced the viability of myeloma cell lines in a time-dependent and concentration-dependent manner associated with G0 /G1 arrest, reduced levels of CDKs 4 and 6, increased p21 levels, and induction of apoptosis...
March 27, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29568956/genome-wide-transcriptional-analysis-of-brd4-regulated-genes-and-pathways-in-human-glioma-u251-cells
#18
Zhanhui Du, Xiuxiang Song, Fangfang Yan, Jingjing Wang, Yuxia Zhao, Shangming Liu
Bromodomain containing 4 (BRD4), a member of the bromodomain and extra-terminal family, has become a promising drug target for numerous types of cancer. BRD4 has been reported to be deregulated in gliomas; however, the precise molecular pathways regulated by BRD4 remained elusive. In the present study, BRD4 expression was silenced in the glioma cell line U251 and the results demonstrated that BRD4 knockdown attenuated cell proliferation and promoted cell apoptosis. A genome-wide analysis of BRD4-regulated transcripts in U251 cells was performed using microarray to reveal the possible molecular mechanism...
March 16, 2018: International Journal of Oncology
https://www.readbyqxmd.com/read/29567272/the-bet-inhibitor-incb054329-reduces-homologous-recombination-efficiency-and-augments-parp-inhibitor-activity-in-ovarian-cancer
#19
Andrew J Wilson, Matthew Stubbs, Phillip Liu, Bruce Ruggeri, Dineo Khabele
OBJECTIVE: Homologous recombination (HR)-proficient ovarian tumors have poorer clinical outcomes and show resistance to poly ADP ribose polymerase inhibitors (PARPi). A subset of HR-proficient ovarian tumors show amplification in bromodomain and extra-terminal (BET) genes such as BRD4. We aimed to test the hypothesis that BRD4 inhibition sensitizes ovarian cancer cells to PARPi by reducing HR efficiency and increasing DNA damage. METHODS: HR-proficient ovarian cancer cell lines (OVCAR-3, OVCAR-4, SKOV-3, UWB1...
March 20, 2018: Gynecologic Oncology
https://www.readbyqxmd.com/read/29566488/structure-based-discovery-and-optimization-of-benzo-d-isoxazole-derivatives-as-potent-and-selective-bet-inhibitors-for-potential-treatment-of-castration-resistant-prostate-cancer-crpc
#20
Maofeng Zhang, Yan Zhang, Ming Song, Xiaoqian Xue, Junjian Wang, Chao Wang, Cheng Zhang, Chenchang Li, Qiuping Xiang, Lingjiao Zou, Xishan Wu, Chun Wu, Baijun Dong, Wei Xue, Yulai Zhou, Hongwu Chen, Donghai Wu, Ke Ding, Yong Xu
The bromodomain and extra-terminal (BET) family proteins have gained increasing interest as drug targets for treatment of castration-resistant prostate cancer (CRPC). Here, we describe the design, optimization and evaluation of benzo[d]isoxazole-containing compounds as potent BET bromodomain inhibitors. Co-crystal structures of the representative inhibitors in complex with BRD4(1) provided solid structural basis for compound optimization. The two most potent compounds, 6i (Y06036) and 7m (Y06137), bound to the BRD4(1) bromodomain with Kd values of 82 and 81 nM, respectively...
March 22, 2018: Journal of Medicinal Chemistry
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