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Jacquelyn O Russell, Sungjin Ko, Harvinder S Saggi, Sucha Singh, Minakshi Poddar, Donghun Shin, Satdarshan P Monga
Bromodomain and extraterminal (BET) proteins recruit key components of basic transcriptional machinery to promote gene expression. Aberrant expression and mutations in BET genes have been identified in many malignancies. Small molecule inhibitors of BET proteins like JQ1 have shown efficacy in preclinical cancer models including affecting growth of hepatocellular carcinoma. BET proteins also regulate cell proliferation in nontumor settings. We recently showed that BET proteins regulate cholangiocyte-driven liver regeneration...
March 12, 2018: American Journal of Pathology
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
Miguel Fontecha-Barriuso, Diego Martin-Sanchez, Olga Ruiz-Andres, Jonay Poveda, Maria Dolores Sanchez-Niño, Lara Valiño-Rivas, Marta Ruiz-Ortega, Alberto Ortiz, Ana Belén Sanz
Epigenetics refers to heritable changes in gene expression patterns not caused by an altered nucleotide sequence, and includes non-coding RNAs and covalent modifications of DNA and histones. This review focuses on functional evidence for the involvement of DNA and histone epigenetic modifications in the pathogenesis of kidney disease and the potential therapeutic implications. There is evidence of activation of epigenetic regulatory mechanisms in acute kidney injury (AKI), chronic kidney disease (CKD) and the AKI-to-CKD transition of diverse aetiologies, including ischaemia-reperfusion injury, nephrotoxicity, ureteral obstruction, diabetes, glomerulonephritis and polycystic kidney disease...
March 9, 2018: Nephrology, Dialysis, Transplantation
Chaoyang Sun, Jun Yin, Yong Fang, Jian Chen, Kang Jin Jeong, Xiaohua Chen, Christopher P Vellano, Zhenlin Ju, Wei Zhao, Dong Zhang, Yiling Lu, Funda Meric-Bernstam, Timothy A Yap, Maureen Hattersley, Mark J O'Connor, Huawei Chen, Stephen Fawell, Shiaw-Yih Lin, Guang Peng, Gordon B Mills
Poly(ADP-ribose) polymerase inhibitors (PARPi) are selectively active in cells with homologous recombination (HR) deficiency (HRD) caused by mutations in BRCA1, BRCA2, and other pathway members. We sought small molecules that induce HRD in HR-competent cells to induce synthetic lethality with PARPi and extend the utility of PARPi. We demonstrated that inhibition of bromodomain containing 4 (BRD4) induced HRD and sensitized cells across multiple tumor lineages to PARPi regardless of BRCA1/2, TP53, RAS, or BRAF mutation status through depletion of the DNA double-stand break resection protein CtIP (C-terminal binding protein interacting protein)...
March 12, 2018: Cancer Cell
Laurent Batiste, Andrea Unzue, Aymeric Dolbois, Fabrice Hassler, Xuan Wang, Nicholas Deerain, Jian Zhu, Dimitrios Spiliotopoulos, Cristina Nevado, Amedeo Caflisch
Expanding the chemical space and simultaneously ensuring synthetic accessibility is of upmost importance, not only for the discovery of effective binders for novel protein classes but, more importantly, for the development of compounds against hard-to-drug proteins. Here, we present AutoCouple, a de novo approach to computational ligand design focused on the diversity-oriented generation of chemical entities via virtual couplings. In a benchmark application, chemically diverse compounds with low-nanomolar potency for the CBP bromodomain and high selectivity against the BRD4(1) bromodomain were achieved by the synthesis of about 50 derivatives of the original fragment...
February 28, 2018: ACS Central Science
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
Srikanth Appikonda, Kaushik N Thakkar, Parantu K Shah, Sharon Y R Dent, Jannik N Andersen, Michelle Craig Barton
Proteins with domains that recognize and bind post-translational modifications (PTMs) of histones are collectively termed epigenetic readers. Numerous interactions between specific reader protein domains and histone PTMs and their regulatory outcomes have been reported, but little is known about how reader proteins may in turn be modulated by these interactions. Tripartite motif-containing protein 24 (TRIM24) is a histone reader aberrantly expressed in multiple cancers. Here, our investigation revealed functional crosstalk between histone acetylation and TRIM24 SUMOylation...
March 9, 2018: Journal of Biological Chemistry
Alejandro Saettone, Jyoti Garg, Jean-Philippe Lambert, Syed Nabeel-Shah, Marcelo Ponce, Alyson Burtch, Cristina Thuppu Mudalige, Anne-Claude Gingras, Ronald E Pearlman, Jeffrey Fillingham
BACKGROUND: The chromatin remodelers of the SWI/SNF family are critical transcriptional regulators. Recognition of lysine acetylation through a bromodomain (BRD) component is key to SWI/SNF function; in most eukaryotes, this function is attributed to SNF2/Brg1. RESULTS: Using affinity purification coupled to mass spectrometry (AP-MS) we identified members of a SWI/SNF complex (SWI/SNFTt ) in Tetrahymena thermophila. SWI/SNFTt is composed of 11 proteins, Snf5Tt , Swi1Tt , Swi3Tt , Snf12Tt , Brg1Tt , two proteins with potential chromatin-interacting domains and four proteins without orthologs to SWI/SNF proteins in yeast or mammals...
March 9, 2018: Epigenetics & Chromatin
Marcia Manterola, Taylor M Brown, Min Young Oh, Corey Garyn, Bryan J Gonzalez, Debra J Wolgemuth
The double bromodomain and extra-terminal domain (BET) proteins are critical epigenetic readers that bind to acetylated histones in chromatin and regulate transcriptional activity and modulate changes in chromatin structure and organization. The testis-specific BET member, BRDT, is essential for the normal progression of spermatogenesis as mutations in the Brdt gene result in complete male sterility. Although BRDT is expressed in both spermatocytes and spermatids, loss of the first bromodomain of BRDT leads to severe defects in spermiogenesis without overtly compromising meiosis...
March 2018: PLoS Genetics
Sara Bolin, Anna Borgenvik, Camilla U Persson, Anders Sundström, Jun Qi, James E Bradner, William A Weiss, Yoon-Jae Cho, Holger Weishaupt, Fredrik J Swartling
Medulloblastoma (MB) is the most common malignant brain tumor in children. MYC genes are frequently amplified and correlate with poor prognosis in MB. BET bromodomains recognize acetylated lysine residues and often promote and maintain MYC transcription. Certain cyclin-dependent kinases (CDKs) are further known to support MYC stabilization in tumor cells. In this report, MB cells were suppressed by combined targeting of MYC expression and MYC stabilization using BET bromodomain inhibition and CDK2 inhibition, respectively...
March 7, 2018: Oncogene
Lara N Gechijian, Dennis L Buckley, Matthew A Lawlor, Jaime M Reyes, Joshiawa Paulk, Christopher J Ott, Georg E Winter, Michael A Erb, Thomas G Scott, Mousheng Xu, Hyuk-Soo Seo, Sirano Dhe-Paganon, Nicholas P Kwiatkowski, Jennifer A Perry, Jun Qi, Nathanael S Gray, James E Bradner
The addressable pocket of a protein is often not functionally relevant in disease. This is true for the multidomain, bromodomain-containing transcriptional regulator TRIM24. TRIM24 has been posited as a dependency in numerous cancers, yet potent and selective ligands for the TRIM24 bromodomain do not exert effective anti-proliferative responses. We therefore repositioned these probes as targeting features for heterobifunctional protein degraders. Recruitment of the VHL E3 ubiquitin ligase by dTRIM24 elicits potent and selective degradation of TRIM24...
March 5, 2018: Nature Chemical Biology
Daniel Gerlach, Ulrike Tontsch-Grunt, Anke Baum, Johannes Popow, Dirk Scharn, Marco H Hofmann, Harald Engelhardt, Onur Kaya, Janina Beck, Norbert Schweifer, Thomas Gerstberger, Johannes Zuber, Fabio Savarese, Norbert Kraut
Bromodomain and extra-terminal (BET) protein inhibitors have been reported as treatment options for acute myeloid leukemia (AML) in preclinical models and are currently being evaluated in clinical trials. This work presents a novel potent and selective BET inhibitor (BI 894999), which has recently entered clinical trials (NCT02516553). In preclinical studies, this compound is highly active in AML cell lines, primary patient samples, and xenografts. HEXIM1 is described as an excellent pharmacodynamic biomarker for target engagement in tumors as well as in blood...
March 1, 2018: Oncogene
Courtney G Sansam, Katarzyna Pietrzak, Blanka Majchrzycka, Maciej A Kerlin, Jingrong Chen, Susannah Rankin, Christopher L Sansam
DNA replication origins in hyperacetylated euchromatin fire preferentially during early S phase. However, how acetylation controls DNA replication timing is unknown. TICRR/TRESLIN is an essential protein required for the initiation of DNA replication. Here, we report that TICRR physically interacts with the acetyl-histone binding bromodomain (BRD) and extraterminal (BET) proteins BRD2 and BRD4. Abrogation of this interaction impairs TICRR binding to acetylated chromatin and disrupts normal S-phase progression...
February 26, 2018: Genes & Development
I Ayelén Ramallo, Victoria Lucía Alonso, Federico Rua, Esteban Serra, Ricardo L E Furlan
A set of chemically engineered extracts enriched in compounds including N-N and N-O fragments in their structures was prepared. Bromodomain binding screening and bioguided fractionation led to the identification of one oxime hit that interacts with TcBDF3 with affinity in the sub-micromolar range and that shows interesting antiparasitic properties against the different life cycle stages of T. cruzi.
February 26, 2018: ACS Combinatorial Science
Jin Gohda, Kazuo Suzuki, Kai Liu, Xialin Xie, Hiroaki Takeuchi, Jun-Ichiro Inoue, Yasushi Kawaguchi, Takaomi Ishida
HIV-1 latent reservoirs harbouring silenced but replication-competent proviruses are a major obstacle against viral eradication in infected patients. The "shock and kill" strategy aims to reactivate latent provirus with latency reversing agents (LRAs) in the presence of antiretroviral drugs, necessitating the development of effective and efficient LRAs. We screened a chemical library for potential LRAs and identified two dual Polo-like kinase (PLK)/bromodomain inhibitors, BI-2536 and BI-6727 (volasertib), which are currently undergoing clinical trials against various cancers...
February 23, 2018: Scientific Reports
Nathan A Berger, Peter C Scacheri
Epigenetic changes in DNA and associated chromatin proteins are increasingly being considered as important mediators of the linkage between obesity and cancer. Although multiple agents, targeted at epigenetic changes, are being tested for therapy of established cancers, this issue of Cancer Prevention Research carries two articles demonstrating that the bromodomain inhibitor I-BET-762 can attenuate adipose tissue-promoted cancers. Although I-BET-762 significantly delayed, rather than completely prevented, the onset of adiposity-promoted transformation and malignancy, these experiments provide important proof of principle for the strategies of targeting epigenetic changes to disrupt the obesity-cancer linkage...
February 23, 2018: Cancer Prevention Research
Grant R Campbell, Rachel S Bruckman, Shayna D Herns, Shweta Joshi, Donald Durden, Stephen A Spector
In this study, we investigated the effect of the dual phosphatidylinositol 3-kinase/mechanistic target of rapamycin (PI3K/MTOR) inhibitor dactolisib (NVP-BEZ235), the PI3K/ MTOR/bromodomain-containing protein 4 (BRD4) inhibitor SF2523 and the BET inhibitor JQ1 on the productive infection of primary macrophages with human immunodeficiency type-1 (HIV). These inhibitors did not alter the initial susceptibility of macrophages to HIV infection. However, dactolisib, JQ1 and SF2523 all decreased HIV replication in macrophages in a dose dependent manner via degradation of intracellular HIV through autophagy...
February 23, 2018: Journal of Biological Chemistry
Tingyu Wu, Guanghui Wang, Wei Chen, Zhehui Zhu, Yun Liu, Zhenyu Huang, Yuji Huang, Peng Du, Yili Yang, Chen-Ying Liu, Long Cui
The bromodomain and extra-terminal domain inhibitors (BETi) are promising epigenetic drugs for the treatment of various cancers through suppression of oncogenic transcription factors. However, only a subset of colorectal cancer (CRC) cells response to BETi. We investigate additional agents that could be combined with BETi to overcome this obstacle. JQ1-resistant CRC cells were used for screening of the effective combination therapies with JQ1. RNA-seq was performed to explore the mechanism of synergistic effect...
February 22, 2018: Cell Death & Disease
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
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