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https://www.readbyqxmd.com/read/29678460/discovery-and-optimization-of-novel-constrained-pyrrolopyridone-bet-family-inhibitors
#1
Steven D Fidanze, Dachun Liu, Robert A Mantei, Lisa A Hasvold, John K Pratt, George S Sheppard, Le Wang, James H Holms, Yujia Dai, Ana Aguirre, Andrew Bogdan, Justin D Dietrich, Jasmina Marjanovic, Chang H Park, Charles W Hutchins, Xiaoyu Lin, Mai H Bui, Xiaoli Huang, Denise Wilcox, Leiming Li, Rongqi Wang, Peter Kovar, Terrance J Magoc, Ganesh Rajaraman, Daniel H Albert, Yu Shen, Warren M Kati, Keith F McDaniel
Novel conformationally constrained BET bromodomain inhibitors have been developed. These inhibitors were optimized in two similar, yet distinct chemical series, the 6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (A) and the 1-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (B). Each series demonstrated excellent activity in binding and cellular assays, and lead compounds from each series demonstrated significant efficacy in in vivo tumor xenograft models.
April 11, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29674981/comparative-effect-of-collaborative-care-pain-medication-and-duloxetine-in-the-treatment-of-major-depressive-disorder-and-comorbid-sub-chronic-pain-results-of-an-exploratory-randomized-placebo-controlled-multicenter-trial-cc-paindip
#2
Eric W de Heer, Jack Dekker, Aartjan T F Beekman, Harm W J van Marwijk, Tjalling J Holwerda, Pierre M Bet, Joost Roth, Lotte Timmerman, Christina M van der Feltz-Cornelis
Objective: Evidence exists for the efficacy of collaborative care (CC) for major depressive disorder (MDD), for the efficacy of the consequent use of pain medication against pain, and for the efficacy of duloxetine against both MDD and neuropathic pain. Their relative effectiveness in comorbid MDD and pain has never been established so far. This study explores the effectiveness of CC with pain medication and duloxetine, and CC with pain medication and placebo, compared with duloxetine alone, on depressive and pain symptoms...
2018: Frontiers in Psychiatry
https://www.readbyqxmd.com/read/29674704/mek-inhibitors-overcome-resistance-to-bet-inhibition-across-a-number-of-solid-and-hematologic-cancers
#3
Anastasia Wyce, Jeanne J Matteo, Shawn W Foley, Daniel J Felitsky, Satyajit R Rajapurkar, Xi-Ping Zhang, Melissa C Musso, Susan Korenchuk, Natalie O Karpinich, Kathryn M Keenan, Melissa Stern, Lijoy K Mathew, Charles F McHugh, Michael T McCabe, Peter J Tummino, Ryan G Kruger, Christopher Carpenter, Olena Barbash
BET inhibitors exhibit broad activity in cancer models, making predictive biomarkers challenging to define. Here we investigate the biomarkers of activity of the clinical BET inhibitor GSK525762 (I-BET; I-BET762) across cancer cell lines and demonstrate that KRAS mutations are novel resistance biomarkers. This finding led us to combine BET with RAS pathway inhibition using MEK inhibitors to overcome resistance, which resulted in synergistic effects on growth and survival in RAS pathway mutant models as well as a subset of cell lines lacking RAS pathway mutations...
April 20, 2018: Oncogenesis
https://www.readbyqxmd.com/read/29657099/design-synthesis-and-biological-evaluation-of-novel-4-phenylisoquinolinone-bet-bromodomain-inhibitors
#4
Michael J Bennett, Yiqin Wu, Amogh Boloor, Jennifer Matuszkiewicz, Shawn M O'Connell, Lihong Shi, Ryan K Stansfield, Joselyn R Del Rosario, James M Veal, David J Hosfield, Jiangchun Xu, Stephen W Kaldor, Jeffrey A Stafford, Juan M Betancort
The bromodomain and extra-terminal (BET) family of epigenetic proteins has attracted considerable attention in drug discovery given its involvement in regulating gene transcription. Screening a focused small molecule library based on the bromodomain pharmacophore resulted in the identification of 2-methylisoquinoline-1-one as a novel BET bromodomain-binding motif. Structure guided SAR exploration resulted in >10,000-fold potency improvement for the BRD4-BD1 bromodomain. Lead compounds exhibited excellent potencies in both biochemical and cellular assays in MYC-dependent cell lines...
April 10, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29656650/discovery-of-tetrahydroquinoxalines-as-bromodomain-and-extra-terminal-domain-bet-inhibitors-with-selectivity-for-the-second-bromodomain
#5
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/29653131/bet-bromodomain-inhibitors-show-anti-papillomavirus-activity-in-vitro-and-block-crpv-wart-growth-in-vivo
#6
Mary A Morse, Karla K Balogh, Sarah A Brendle, Colin A Campbell, Mao X Chen, Rebecca C Furze, Isobel L Harada, Ian D Holyer, Umesh Kumar, Kevin Lee, Rab K Prinjha, Martin Rüdiger, Jon Seal, Simon Taylor, Jason Witherington, Neil D Christensen
The DNA papillomaviruses infect squamous epithelium and can cause persistent, benign and sometimes malignant hyperproliferative lesions. Effective antiviral drugs to treat human papillomavirus (HPV) infection are lacking and here we investigate the anti-papillomavirus activity of novel epigenetic targeting drugs, BET bromodomain inhibitors. Bromodomain and Extra-Terminal domain (BET) proteins are host proteins which regulate gene transcription, they bind acetylated lysine residues in histones and non-histone proteins via bromodomains, functioning as scaffold proteins in the formation of transcriptional complexes at gene regulatory regions...
April 10, 2018: Antiviral Research
https://www.readbyqxmd.com/read/29650805/co-targeting-bet-and-mek-as-salvage-therapy-for-mapk-and-checkpoint-inhibitor-resistant-melanoma
#7
Ileabett M Echevarría-Vargas, Patricia I Reyes-Uribe, Adam N Guterres, Xiangfan Yin, Andrew V Kossenkov, Qin Liu, Gao Zhang, Clemens Krepler, Chaoran Cheng, Zhi Wei, Rajasekharan Somasundaram, Giorgos Karakousis, Wei Xu, Jennifer Jd Morrissette, Yiling Lu, Gordon B Mills, Ryan J Sullivan, Miao Benchun, Dennie T Frederick, Genevieve Boland, Keith T Flaherty, Ashani T Weeraratna, Meenhard Herlyn, Ravi Amaravadi, Lynn M Schuchter, Christin E Burd, Andrew E Aplin, Xiaowei Xu, Jessie Villanueva
Despite novel therapies for melanoma, drug resistance remains a significant hurdle to achieving optimal responses. NRAS-mutant melanoma is an archetype of therapeutic challenges in the field, which we used to test drug combinations to avert drug resistance. We show that BET proteins are overexpressed in NRAS-mutant melanoma and that high levels of the BET family member BRD4 are associated with poor patient survival. Combining BET and MEK inhibitors synergistically curbed the growth of NRAS -mutant melanoma and prolonged the survival of mice bearing tumors refractory to MAPK inhibitors and immunotherapy...
April 12, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29642362/re-prostate-cancer-associated-spop-mutations-confer-resistance-to-bet-inhibitors-through-stabilization-of-brd4
#8
Anthony Atala
No abstract text is available yet for this article.
April 2018: Journal of Urology
https://www.readbyqxmd.com/read/29625382/phthalimide-conjugations-for-the-degradation-of-oncogenic-pi3k
#9
Wenlu Li, Chunmei Gao, Lei Zhao, Zigao Yuan, Yuzong Chen, Yuyang Jiang
PI3K/Akt/mTOR pathway is crucial for carcinogenesis and its inhibitors have made a great progress in cancer treatment. However, there is still a great developing space for PI3K inhibitors as the acquired drug resistance hindered their application in clinical. Proteolysis-targeting chimeras (PROTACs) with the potential to handle the challenges faced in drug development could be an alternative therapeutic strategy. Moreover, the past two years have witnessed remarkable advances in the development of phthalimide conjugation as a strategy for the degradation instead of inhibition of the targets, including BET family proteins, Sirtuin 2, CDK 9, Smad 3, and BCR-ABL proteins...
March 26, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29622725/slam-seq-defines-direct-gene-regulatory-functions-of-the-brd4-myc-axis
#10
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/29605436/the-role-of-za-channel-water-mediated-interactions-in-the-design-of-bromodomain-selective-bet-inhibitors
#11
Nagakumar Bharatham, Peter J Slavish, Brandon M Young, Anang A Shelat
The Bromodomain and Extra-Terminal domain (BET) family of proteins are involved in the regulation of gene transcription, and their dysregulation is implicated in several diseases including cancer. BET proteins contain two tandem bromodomains (BD1 and BD2) that independently recognize acetylated-lysine residues and appear to have distinct biological roles. We compared several published co-crystal structures and found five positions near the substrate binding pocket that vary between BET bromodomains. One position located in the ZA loop has unique properties...
March 22, 2018: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/29603290/bet-ting-on-nrf2-how-nrf2-signaling-can-influence-the-therapeutic-activities-of-bet-protein-inhibitors
#12
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/29600711/jq-1-inhibits-colon-cancer-proliferation-via-suppressing-wnt-%C3%AE-catenin-signaling-and-mir-21
#13
Yan Zhang, Suli Tian, Jidong Xiong, Yongxu Zhou, Hongyu Song, Chang Liu
Bromodoamin and extraterminal (BET) protein inhibitors are a novel class of cancer therapeutics. Here we aim to investigate the efficacy and mechanism of JQ-1, a potent BET inhibitor, in colon cancer therapy. JQ-1 was used to treat SW480 colon cancer mouse xenografts. Tumor size and mouse survival were recorded. Cell apoptosis was evaluated by Annex V-FIC/PI flow cytometry. ChIP-q-PCR analysis was used to assess the H3K27 trimethylation (H3K27m3) of the p16 promoter. Wnt signaling was evaluated by Nkd2 and β-catenin levels...
March 30, 2018: Chemical Research in Toxicology
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
#14
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/29567837/the-brd3-et-domain-recognizes-a-short-peptide-motif-through-a-mechanism-that-is-conserved-across-chromatin-remodelers-and-transcriptional-regulators
#15
Dorothy C Wai, Taylor N Szyszka, Amy E Campbell, Cherry Kwong, Lorna E Wilkinson-White, Ana P G Silva, Jason K K Low, Ann H Kwan, Roland Gamsjaeger, James N Chalmers, Wayne M Patrick, Bin Lu, Christopher R Vakoc, Gerd Blobel, Joel P Mackay
Members of the bromodomain and extra-terminal domain (BET) family of proteins (bromodomain-containing (BRD) 2, 3, 4 and T) are widely expressed and highly conserved regulators of gene expression in eukaryotes. These proteins have been intimately linked to human disease and more than a dozen clinical trials are currently underway to test BET-protein inhibitors as modulators of cancer therapies. However, although it is clear that these proteins use their bromodomains to bind both histones and transcription factors bearing acetylated lysine residues, the molecular mechanisms by which BET-family proteins regulate gene expression are not well defined...
March 22, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29567778/bet-inhibition-by-jq1-promotes-proliferation-and-self-renewal-capacity-of-hematopoietic-stem-cells
#16
Mark Wroblewski, Marina Scheller-Wendorff, Florian Udonta, Raimund Bauer, Jara Schlichting, Lin Zhao, Isabel Ben Batalla, Victoria Gensch, Sarina Päsler, Lei Wu, Marek Wanior, Hanna Taipaleenmäki, Simona Bolamperti, Zeynab Najafova, Klaus Pantel, Carsten Bokemeyer, Jun Qi, Eric Hesse, Stefan Knapp, Steven Johnsen, Sonja Loges
Although inhibitors of bromodomain and extra terminal domain (BET) proteins show promising clinical activity in different hematologic malignancies, a systematic analysis of the consequences of pharmacological BET inhibition on healthy hematopoietic (stem) cells is outstanding. We found that JQ1 treatment decreases the numbers of pre-, immature and mature B cells while numbers of early pro-B cells remain constant. In addition, it increases apoptosis in T cells, all together leading to reduced cellularity in thymus, bone marrow and spleen...
March 22, 2018: Haematologica
https://www.readbyqxmd.com/read/29567272/the-bet-inhibitor-incb054329-reduces-homologous-recombination-efficiency-and-augments-parp-inhibitor-activity-in-ovarian-cancer
#17
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
#18
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
https://www.readbyqxmd.com/read/29566379/apabetalone-mediated-epigenetic-modulation-is-associated-with-favorable-kidney-function-and-alkaline-phosphatase-profile-in-patients-with-chronic-kidney-disease
#19
Ewelina Kulikowski, Christopher Halliday, Jan Johansson, Mike Sweeney, Kenneth Lebioda, Norman Wong, Mathias Haarhaus, Vincent Brandenburg, Srinivasan Beddhu, Marcello Tonelli, Carmine Zoccali, Kamyar Kalantar-Zadeh
BACKGROUND/AIMS: The association between serum alkaline phosphatase (ALP) with adverse cardiovascular outcomes, in Chronic Kidney Disease (CKD) patients has previously been reported and may be a result of increased vascular calcification and inflammation. Here we report, for the first time, the effects of pharmacologic epigenetic modulation on levels of ALP and kidney function via a novel oral small molecule BET inhibitor, apabetalone, in CKD patients. METHODS: A post-hoc analysis evaluated patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1...
March 16, 2018: Kidney & Blood Pressure Research
https://www.readbyqxmd.com/read/29561307/synergistic-in-vitro-effects-of-combining-an-antiglycolytic-3-bromopyruvate-and-a-bromodomain-4-inhibitor-on-u937-myeloid-leukemia-cells
#20
Nicolette Kapp, Xiao X Stander, Barend A Stander
This project investigated the in-vitro effects of a glycolytic inhibitor, 3-bromopyruvate (3-BrP), in combination with and a new in silico-designed inhibitor of the bromodomain-4 (BRD-4) protein, ITH-47, on the U937 acute myeloid leukemia cell line. 3-BrP is an agent that targets the altered metabolism of cancer cells by interfering with glucose metabolism in the glycolytic pathway. ITH-47 is an acetyl-lysine inhibitor that displaces bromdomain 4 proteins from chromatin by competitively binding to the acetyl-lysine recognition pocket of this bromodomain and extraterminal (BET) BRD protein, thereby preventing transcription of cancer-associated genes and further cell growth...
March 20, 2018: Anti-cancer Drugs
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