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Jonathan Welti, Adam Sharp, Wei Yuan, David I Dolling, Daniel Nava Rodrigues, Ines Figueiredo, Veronica Gil, Antje Neeb, Matthew Clarke, George Seed, Mateus Crespo, Semini Sumanasuriya, Jian Ning, Eleanor Knight, Jeffrey C Francis, Ashley Hughes, Wendy S Halsey, Alec Paschalis, Ram S Mani, Ganesh V Raj, Steve Plymate, Suzanne Carreira, Gunther Boysen, Arul M Chinnaiyan, Amanda Swain, Johann S de Bono
PURPOSE:  Persistent androgen receptor (AR) signaling drives castration resistant prostate cancer (CRPC) and confers resistance to AR targeting therapies. Novel therapeutic strategies to overcome this are urgently required. We evaluated how bromodomain and extra-terminal (BET) protein inhibitors (BETi) abrogate aberrant AR signaling in CRPC. EXPERIMENTAL DESIGN:  We determined associations between BET expression, AR driven transcription and patient outcome; and the effect and mechanism by which chemical BETi (JQ1 and GSK1210151A; I-BET151) and BET family protein knockdown regulates AR-V7 expression and AR signaling in prostate cancer (PC) models...
March 19, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Qiuping Xiang, Yan Zhang, Jiaguo Li, Xiaoqian Xue, Chao Wang, Ming Song, Cheng Zhang, Rui Wang, Chenchang Li, Chun Wu, Yulai Zhou, Xiaohong Yang, Guohui Li, Ke Ding, Yong Xu
Prostate cancer is a commonly diagnosed cancer and a leading cause of cancer-related deaths. The bromodomain and extra terminal domain (BET) family proteins have emerged as potential therapeutic targets for the treatment of castration-resistant prostate cancer. A series of 2,2-dimethyl-2 H -benzo[ b ][1,4]oxazin-3(4 H )-one derivatives were designed and synthesized as selective bromodomain containing protein 4 (BRD4) inhibitors. The compounds potently inhibit BRD4(1) with nanomolar IC50 values and exhibit high selectivity over most non-BET subfamily members...
March 8, 2018: ACS Medicinal Chemistry Letters
Erina Tonouchi, Yasuyuki Gen, Tomoki Muramatsu, Hidekazu Hiramoto, Kousuke Tanimoto, Jun Inoue, Johji Inazawa
Bromodomain Containing 4 (BRD4) mediates transcriptional elongation of the oncogene MYC by binding to acetylated histones. BRD4 has been shown to play a critical role in tumorigenesis in several cancers, and the BRD4-NUT fusion gene is a driver of NUT midline carcinoma (NMC), a rare but highly lethal cancer. microRNAs (miRNAs) are endogenous small non-coding RNAs that suppress target gene expression by binding to complementary mRNA sequences. Here, we show that miR-3140, which was identified as a novel tumor suppressive miRNA by function-based screening of a library containing 1090 miRNA mimics, directly suppressed BRD4 by binding to its coding sequence (CDS)...
March 14, 2018: Scientific Reports
Jianping Hu, Yingqing Wang, Yanlian Li, Danyan Cao, Lin Xu, ShanShan Song, Mohammadali Soleimani Damaneh, Jian Li, Yuelei Chen, Xin Wang, Lin Chen, Jingkang Shen, Zehong Miao, Bing Xiong
Recently, several kinase inhibitors were found to also inhibit bromodomains, providing a new strategy for the discovery of bromodomain inhibitors. Along this line, starting from PLK1-BRD4 dual inhibitor BI-2536, we discovered a new series of dihydroquinoxalin-2(1H)-one with aniline and indoline WPF binders as selective BRD4 inhibitors. They showed better BRD4-BD1 potency and negligible PLK1 kinase activity comparing with BI-2536. Additionally, dihydroquinoxalin-2(1H)-ones containing indoline group showed profound activities in molecular and cellular based assays...
February 24, 2018: European Journal of Medicinal Chemistry
Morgan Preziosi, Minakshi Poddar, Sucha Singh, Satdarshan P Monga
Activation of the Wnt/β-catenin signaling is reported in large subsets of hepatocellular carcinoma (HCC). Upregulationof Wnt genes is one contributing mechanism. In the current study, we sought to address the role of hepatocyte-derived Wnts in a model of hepatic injury, fibrosis and carcinogenesis. We subjected hepatocyte-specific Wntless knockout mice (HP-KO), unable to secrete Wnts from hepatocytes, and littermate controls (HP-CON), to diethylnitrosamine and carbon tetrachloride (DEN/CCl4) and harvested at 3, 5, and 6 months for histological and molecular analysis...
March 8, 2018: Gene Expression
Emilia Kuuluvainen, Eva Domènech-Moreno, Elina H Niemelä, Tomi P Mäkelä
In cancer, oncogene activation is partly mediated by acquired super-enhancers therefore representing potential targets for inhibition. Super-enhancers are enriched for BRD4 and Mediator and both BRD4 and the Mediator MED12 subunit are disproportionally required for expression of super-enhancer associated genes in stem cells. Here, we find that depletion of Mediator kinase module subunits MED12, and MED13 with MED13L, can be used to reduce expression of cancer acquired super-enhancer genes such as MYC in colon cancer cells with a concomitant decrease in proliferation...
March 5, 2018: Molecular and Cellular Biology
Duncan C Miller, Mathew P Martin, Santosh Adhikari, Alfie Brennan, Jane A Endicott, Bernard T Golding, Ian R Hardcastle, Amy Heptinstall, Stephen Hobson, Claire Jennings, Lauren Molyneux, Yvonne Ng, Stephen R Wedge, Martin E M Noble, Celine Cano
ATAD2 is an ATPase that is overexpressed in a variety of cancers and associated with a poor patient prognosis. This protein has been suggested to function as a cofactor for a range of transcription factors, including the proto-oncogene MYC and the androgen receptor. ATAD2 comprises an ATPase domain, implicated in chromatin remodelling, and a bromodomain which allows it to interact with acetylated histone tails. Dissection of the functional roles of these two domains would benefit from the availability of selective, cell-permeable pharmacological probes...
February 22, 2018: Organic & Biomolecular Chemistry
Carlos Murga-Zamalloa, Avery Polk, Walter Hanel, Pinki Chowdhury, Noah Brown, Alexandra C Hristov, Nathanael G Bailey, Tianjiao Wang, Tycel Phillips, Sumana Devata, Pradeep Poonnen, Juan Gomez-Gelvez, Kedar V Inamdar, Ryan A Wilcox
Survival following anthracycline-based chemotherapy remains poor among patients with most T-cell lymphoproliferative disorders. This may be attributed, at least in part, to cell-autonomous mechanisms of chemotherapy resistance observed in these lymphomas, including the loss of important tumor suppressors and the activation of signaling cascades that culminate in the expression and activation of transcription factors promoting cell growth and survival. Therefore, the identification of novel therapeutic targets is needed...
December 29, 2017: Oncotarget
Jian Wang, Fangzheng Zhou, Zhenyu Li, Hong Mei, Ye Wang, Hong Ma, Liangliang Shi, Ai Huang, Tao Zhang, Zhenyu Lin, Gang Wu
Radiation-induced lung injury has restricted radiotherapy for thoracic cancer. The purpose of this study was to investigate the radioprotective effects of bromodomain and extra terminal (BET) inhibitor JQ1 in a murine model of pulmonary damage. Chest computed tomography (CT) was performed in a rat model after 20 Gy radiation of the right thorax. And histological evaluation and protein expressions of irradiated tissue were analyzed to confirm the potential anti-fibrosis effect of JQ1 and its underlying mechanisms...
January 17, 2018: Scientific Reports
Erik Abner, Mateusz Stoszko, Lei Zeng, Heng-Chang Chen, Andrea Izquierdo-Bouldstridge, Tsuyoshi Konuma, Eduard Zorita, Elisa Fanunza, Qiang Zhang, Tokameh Mahmoudi, Ming-Ming Zhou, Guillaume J Filion, Albert Jordan
Upon HIV-1 infection, a reservoir of latently infected resting T cells prevents the eradication of the virus from patients. To achieve complete depletion, the existing virus-suppressing antiretroviral therapy must be combined with drugs that reactivate the dormant viruses. We previously described a novel chemical scaffold compound, MMQO (8-methoxy-6-methylquinolin-4-ol) that is able to reactivate viral transcription in several models of HIV latency including J-Lat cells through an unknown mechanism. MMQO potentiates the activity of known latency-reversing agents (LRAs) or 'shock' drugs such as PKC agonists or HDAC inhibitors...
January 17, 2018: Journal of Virology
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
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
Kwong Wah Lai, F Anthony Romero, Vickie Tsui, Maureen H Beresini, Gladys de Leon Boenig, Sarah M Bronner, Kevin Chen, Zhongguo Chen, Edna F Choo, Terry D Crawford, Patrick Cyr, Susan Kaufman, Yingjie Li, Jiangpeng Liao, Wenfeng Liu, Justin Ly, Jeremy Murray, Weichao Shen, John Wai, Fei Wang, Caicai Zhu, Xiaoyu Zhu, Steven Magnuson
A novel, potent, and orally bioavailable inhibitor of the bromodomain of CBP, compound 35 (GNE-207), has been identified through SAR investigations focused on optimizing al bicyclic heteroarene to replace the aniline present in the published GNE-272 series. Compound 35 has excellent CBP potency (CBP IC50  = 1 nM, MYC EC50  = 18 nM), a selectively index of >2500-fold against BRD4(1), and exhibits a good pharmacokinetic profile.
January 1, 2018: Bioorganic & Medicinal Chemistry Letters
Natalia Moreno, Till Holsten, Julius Mertins, Annabelle Zhogbi, Pascal Johann, Marcel Kool, Michael Meisterernst, Kornelius Kerl
Rhabdoid tumors are caused by the deletion of SMARCB1, whose protein encodes the SMARCB1 subunit of the chromatin remodeling complex SWI/SNF that is involved in global chromatin organization and gene expression control. Simultaneously inhibiting the main players involved in the deregulated transcription machinery is a promising option for preventing exaggerated tumor cell proliferation and survival as it may bypass compensatory mechanisms. In support of this hypothesis, we report efficient impairment of cellular proliferation and strong induction of cell death elicited by inhibition of bromodomain protein BRD4 and transcription kinase CDK9 using small molecular compounds...
October 17, 2017: Oncotarget
Gang Shen, Minjun Jiang, Jinxian Pu
Bromodomain-containing protein 4 (BRD4) and phosphatidylinositol 3-kinase (PI3K) are both key oncogenic proteins in human prostate cancer. In the current study, we examined the anti-prostate cancer cell activity by SF2523, a BRD4 and PI3K dual inhibitor. We showed that SF2523 potently inhibited survival and proliferation of the primary human prostate cancer cells. SF2523 induced profound apoptosis activation in prostate cancer cells. The dual inhibitor was yet non-cytotoxic to the prostate epithelial cells...
November 10, 2017: Biochemical and Biophysical Research Communications
Minjin Yoo, Miyoun Yoo, Ji Eun Kim, Heung Kyoung Lee, Chong Ock Lee, Chi Hoon Park, Kwan-Young Jung
Bromodomain-containing protein 4 (BRD4) is known to regulate the expression of c-Myc to control the proliferation of cancer cells. Therefore, development of small-molecule inhibitors targeting the bromodomain has been widely studied. However, some clinical trials on BRD4 inhibitors have shown its drawbacks such as toxicity including the loss of organ weight. Here, we report the development of the novel and promising scaffold, 1H-indazol-4,7-dione, as a bromodomain inhibitor and synthesized derivatives for the inhibition of binding of bromodomain to acetylated histone peptide...
November 4, 2017: Archives of Pharmacal Research
Hiroshi Minato, Eriko Kobayashi, Satoko Nakada, Nozomu Kurose, Mio Tanaka, Yukichi Tanaka, Shioto Suzuki, Fumihiko Tanioka, Yutaka Saikawa, Takaki Miwa, Takayuki Nojima
Nuclear protein in testis (NUT) carcinoma is a rare malignant neoplasm with an undifferentiated morphology. Its diagnosis is often difficult, especially as the sinonasal tract gives rise to many tumors with undifferentiated morphologies. Not many cases of sinonasal NUT carcinomas have been reported, and its clinicopathological features have not been sufficiently clarified. In this study, we performed a clinicopathological study of 4 patients with sinonasal NUT carcinoma, including wide-ranging immunohistochemical tests and cytogenetic analyses using fluorescence in situ hybridization and DNA sequencing...
October 24, 2017: Human Pathology
Tie Xiang, Jin-Yu Bai, Chang She, Dao-Jiang Yu, Xiao-Zhong Zhou, Tian-Lan Zhao
The present study examined the expression and biological functions of bromodomain-containing protein 4 (BRD4) in skin squamous cell carcinoma (SCC) cells. Our results show that BRD4 mRNA and protein expression was upregulated in human skin SCC cells, as compared to its level in the normal skin keratinocytes and fibroblasts. Treatment with BRD4 inhibitors, JQ1 and CPI203, resulted in proliferation inhibition, apoptosis and cell cycle arrest in both established (A431 cell line) and primary skin SCC cells. Furthermore, BRD4 knockdown (by targeted shRNAs) or knockout (by CRISPR/Cas9) largely inhibited A431 cell proliferation...
January 2018: Cellular Signalling
Danka Cholujova, Zdenka Bujnakova, Erika Dutkova, Teru Hideshima, Richard W Groen, Constantine S Mitsiades, Paul G Richardson, David M Dorfman, Peter Balaz, Kenneth C Anderson, Jana Jakubikova
Multiple myeloma (MM), a B cell malignancy characterized by clonal proliferation of plasma cells in the bone marrow, remains incurable despite the use of novel and conventional therapies. In this study, we demonstrated MM cell cytotoxicity triggered by realgar (REA; As4 S4 ) nanoparticles (NREA) versus Arsenic trioxide (ATO) against MM cell lines and patient cells. Both NREA and ATO showed in vivo anti-MM activity, resulting in significantly decreased tumour burden. The anti-MM activity of NREA and ATO is associated with apoptosis, evidenced by DNA fragmentation, depletion of mitochondrial membrane potential, cleavage of caspases and anti-apoptotic proteins...
December 2017: British Journal of Haematology
Sanchari Bhattacharyya, Kith Pradhan, Nathaniel Campbell, Jozef Mazdo, Aparna Vasantkumar, Shahina Maqbool, Tushar D Bhagat, Sonal Gupta, Masako Suzuki, Yiting Yu, John M Greally, Ulrich Steidl, James Bradner, Meelad Dawlaty, Lucy Godley, Anirban Maitra, Amit Verma
Transcriptional deregulation of oncogenic pathways is a hallmark of cancer and can be due to epigenetic alterations. 5-Hydroxymethylcytosine (5-hmC) is an epigenetic modification that has not been studied in pancreatic cancer. Genome-wide analysis of 5-hmC-enriched loci with hmC-seal was conducted in a cohort of low-passage pancreatic cancer cell lines, primary patient-derived xenografts, and pancreatic controls and revealed strikingly altered patterns in neoplastic tissues. Differentially hydroxymethylated regions preferentially affected known regulatory regions of the genome, specifically overlapping with known H3K4me1 enhancers...
November 2017: Genome Research
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