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Cancer AND BRD4

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https://www.readbyqxmd.com/read/28339196/discovery-of-a-small-molecule-degrader-of-bromodomain-and-extra-terminal-bet-proteins-with-picomolar-cellular-potencies-and-capable-of-achieving-tumor-regression
#1
Bing Zhou, Jiantao Hu, Fuming Xu, Zhuo Chen, Longchuan Bai, Ester Fernandez-Salas, Mei Lin, Liu Liu, Chao-Yie Yang, Yujun Zhao, Donna McEachern, Sally Przybranowski, Bo Wen, Duxin Sun, Shaomeng Wang
The bromodomain and extra-terminal (BET) family proteins, consisting of BRD2, BRD3, BRD4, and testis-specific BRDT members, are epigenetic "readers" and play a key role in the regulation of gene transcription. BET proteins are considered to be attractive therapeutic targets for cancer and other human diseases. Recently, heterobifunctional small-molecule BET degraders have been designed based upon the proteolysis targeting chimera (PROTAC) concept to induce BET protein degradation. Herein, we present our design, synthesis, and evaluation of a new class of PROTAC BET degraders...
March 24, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28336808/potent-dual-bet-bromodomain-kinase-inhibitors-as-value-added-multi-targeted-chemical-probes-and-cancer-therapeutics
#2
Stuart W Ember, Que T Lambert, Norbert Berndt, Steven Gunawan, Muhammad Ayaz, Marilena Tauro, Jin-Yi Zhu, Paula J Cranfill, Patricia Greninger, Conor C Lynch, Cyril H Benes, Harshani R Lawrence, Gary W Reuther, Nicholas J Lawrence, Ernst Schonbrunn
Synergistic action of kinase and BET bromodomain inhibitors in cell killing has been reported for a variety of cancers. Using the chemical scaffold of the JAK2 inhibitor TG101348 we developed and characterized single agents which potently and simultaneously inhibit BRD4 and a specific set of oncogenic tyrosine kinases including JAK2, FLT3, RET, and ROS1. Lead compounds showed on-target inhibition in several blood cancer cell lines and were highly efficacious at inhibiting the growth of hematopoietic progenitor cells from myeloproliferative neoplasm (MPN) patients...
March 23, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28314513/design-synthesis-and-biological-evaluation-of-7-methylimidazo-1-5-a-pyrazin-8-7h-one-derivatives-as-brd4-inhibitors
#3
Leilei Zhao, Yifei Yang, Yahui Guo, Lingyun Yang, Jian Zhang, Jinpei Zhou, Huibin Zhang
BRD4 is an attractive target for antitumor due to its important role in regulation of gene transcription. In this paper, we synthesized a series of 7-methylimidazo[1,5-a]pyrazin-8(7H)-one derivatives as potent BRD4 inhibitors and evaluated their BRD4 inhibitory activities in vitro and anti-proliferation effects on tumor cells. Gratifyingly, compound 10j exhibited robust potency of BRD4(1) and BRD4(2) inhibition with IC50 values of 130 and 76nM respectively. Docking studies were performed to explain the structure-activity relationship...
March 7, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28249162/bet-bromodomain-inhibitors-engage-the-host-immune-system-and-regulate-expression-of-the-immune-checkpoint-ligand-pd-l1
#4
Simon J Hogg, Stephin J Vervoort, Sumit Deswal, Christopher J Ott, Jason Li, Leonie A Cluse, Paul A Beavis, Phillip K Darcy, Benjamin P Martin, Andrew Spencer, Anna K Traunbauer, Irina Sadovnik, Karin Bauer, Peter Valent, James E Bradner, Johannes Zuber, Jake Shortt, Ricky W Johnstone
BET inhibitors (BETi) target bromodomain-containing proteins and are currently being evaluated as anti-cancer agents. We find that maximal therapeutic effects of BETi in a Myc-driven B cell lymphoma model required an intact host immune system. Genome-wide analysis of the BETi-induced transcriptional response identified the immune checkpoint ligand Cd274 (Pd-l1) as a Myc-independent, BETi target-gene. BETi directly repressed constitutively expressed and interferon-gamma (IFN-γ) induced CD274 expression across different human and mouse tumor cell lines and primary patient samples...
February 28, 2017: Cell Reports
https://www.readbyqxmd.com/read/28237246/sipa1-promotes-invasion-and-migration-in-human-oral-squamous-cell-carcinoma-by-itgb1-and-mmp7
#5
Toshikazu Takahara, Atsushi Kasamatsu, Masanobu Yamatoji, Manabu Iyoda, Hiroki Kasama, Tomoaki Saito, Shin Takeuchi, Yosuke Endo-Sakamoto, Masashi Shiiba, Hideki Tanzawa, Katsuhiro Uzawa
Signal-induced proliferation-associated protein 1 (SIPA1) is known to be a GTPase activating protein. Overexpressed SIPA1 is related to metastatic progression in breast and prostate cancers; however, the relevance of SIPA1 in oral squamous cell carcinoma (OSCC) is still unknown. The aim of this study was to examine SIPA1 expression and its functional mechanisms in OSCC. SIPA1 mRNA and protein expressions were analyzed by quantitative reverse transcriptase-polymerase chain reaction, Western blot analysis, and immunohistochemistry...
March 15, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28215221/targeting-chromatin-remodeling-in-inflammation-and-fibrosis
#6
J Yang, B Tian, A R Brasier
Mucosal surfaces of the human body are lined by a contiguous epithelial cell surface that forms a barrier to aerosolized pathogens. Specialized pattern recognition receptors detect the presence of viral pathogens and initiate protective host responses by triggering activation of the nuclear factor κB (NFκB)/RelA transcription factor and formation of a complex with the positive transcription elongation factor (P-TEFb)/cyclin-dependent kinase (CDK)9 and Bromodomain-containing protein 4 (BRD4) epigenetic reader...
2017: Advances in Protein Chemistry and Structural Biology
https://www.readbyqxmd.com/read/28205554/the-oncoppi-network-of-cancer-focused-protein-protein-interactions-to-inform-biological-insights-and-therapeutic-strategies
#7
Zenggang Li, Andrei A Ivanov, Rina Su, Valentina Gonzalez-Pecchi, Qi Qi, Songlin Liu, Philip Webber, Elizabeth McMillan, Lauren Rusnak, Cau Pham, Xiaoqian Chen, Xiulei Mo, Brian Revennaugh, Wei Zhou, Adam Marcus, Sahar Harati, Xiang Chen, Margaret A Johns, Michael A White, Carlos Moreno, Lee A D Cooper, Yuhong Du, Fadlo R Khuri, Haian Fu
As genomics advances reveal the cancer gene landscape, a daunting task is to understand how these genes contribute to dysregulated oncogenic pathways. Integration of cancer genes into networks offers opportunities to reveal protein-protein interactions (PPIs) with functional and therapeutic significance. Here, we report the generation of a cancer-focused PPI network, termed OncoPPi, and identification of >260 cancer-associated PPIs not in other large-scale interactomes. PPI hubs reveal new regulatory mechanisms for cancer genes like MYC, STK11, RASSF1 and CDK4...
February 16, 2017: Nature Communications
https://www.readbyqxmd.com/read/28195723/drug-discovery-targeting-bromodomain-containing-protein-4
#8
Zhiqing Liu, Pingyuan Wang, Haiying Chen, Eric A Wold, Bing Tian, Allan R Brasier, Jia Zhou
BRD4, the most extensively studied member of the BET family, is an epigenetic regulator that localizes to DNA via binding to acetylated histones and controls the expression of therapeutically important gene regulatory networks through the recruitment of transcription factors to form mediator complexes, phosphorylating RNA polymerase II, and by its intrinsic histone acetyltransferase activity. Disrupting the protein-protein interactions between BRD4 and acetyl-lysine has been shown to effectively block cell proliferation in cancer, cytokine production in acute inflammation, and so forth...
March 2, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28194432/bet-inhibitors-block-pancreatic-stellate-cell-collagen-i-production-and-attenuate-fibrosis-in-vivo
#9
Krishan Kumar, Brian T DeCant, Paul J Grippo, Rosa F Hwang, David J Bentrem, Kazumi Ebine, Hidayatullah G Munshi
The fibrotic reaction, which can account for over 70%-80% of the tumor mass, is a characteristic feature of human pancreatic ductal adenocarcinoma (PDAC) tumors. It is associated with activation and proliferation of pancreatic stellate cells (PSCs), which are key regulators of collagen I production and fibrosis in vivo. In this report, we show that members of the bromodomain and extraterminal (BET) family of proteins are expressed in primary PSCs isolated from human PDAC tumors, with BRD4 positively regulating, and BRD2 and BRD3 negatively regulating, collagen I expression in primary cancer-associated PSCs...
February 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28174254/the-essential-transcriptional-function-of-brd4-in-acute-myeloid-leukemia
#10
Jae-Seok Roe, Christopher R Vakoc
Acute myeloid leukemia (AML) is often initiated by genetic alterations of machineries that regulate chromatin and transcription, thereby blocking cell differentiation. Such mechanisms may also render leukemia cells vulnerable to perturbations of transcriptional regulators, which includes small molecules targeting the coactivator protein BRD4. Numerous studies have validated BRD4 as a therapeutic target in diverse subtypes of AML; however, the vital function of BRD4 in this disease is only beginning to be understood...
February 7, 2017: Cold Spring Harbor Symposia on Quantitative Biology
https://www.readbyqxmd.com/read/28154167/in-vivo-knockdown-of-pathogenic-proteins-via-specific-and-nongenetic-iap-dependent-protein-erasers-snipers
#11
Nobumichi Ohoka, Keiichiro Okuhira, Masahiro Ito, Katsunori Nagai, Norihito Shibata, Takayuki Hattori, Osamu Ujikawa, Kenichiro Shimokawa, Osamu Sano, Ryokichi Koyama, Hisashi Fujita, Mika Teratani, Hirokazu Matsumoto, Yasuhiro Imaeda, Hiroshi Nara, Nobuo Cho, Mikihiko Naito
Many diseases, especially cancers, result from aberrant or over-expression of pathogenic proteins. Specific inhibitors against these proteins have shown remarkable therapeutic effects, but are limited mainly to enzymes. An alternative approach that may have utility in drug development relies on selective degradation of pathogenic proteins via small, chimeric molecules linking an E3 ubiquitin ligase to the targeted protein for proteasomal degradation. To this end, we recently developed a protein-knockdown system based on hybrid small-molecule SNIPERs (Specific and Nongenetic IAP-dependent Protein Erasers) that recruit inhibitor of apoptosis protein (IAP) ubiquitin ligases to specifically degrade targeted proteins...
February 2, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28137841/dual-activity-pi3k-brd4-inhibitor-for-the-orthogonal-inhibition-of-myc-to-block-tumor-growth-and-metastasis
#12
Forest H Andrews, Alok R Singh, Shweta Joshi, Cassandra A Smith, Guillermo A Morales, Joseph R Garlich, Donald L Durden, Tatiana G Kutateladze
MYC is a major cancer driver but is documented to be a difficult therapeutic target itself. Here, we report on the biological activity, the structural basis, and therapeutic effects of the family of multitargeted compounds that simultaneously disrupt functions of two critical MYC-mediating factors through inhibiting the acetyllysine binding of BRD4 and the kinase activity of PI3K. We show that the dual-action inhibitor impairs PI3K/BRD4 signaling in vitro and in vivo and affords maximal MYC down-regulation...
February 14, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28108460/enhancer-remodeling-during-adaptive-bypass-to-mek-inhibition-is-attenuated-by-pharmacologic-targeting-of-the-p-tefb-complex
#13
Jon S Zawistowski, Samantha M Bevill, Daniel R Goulet, Timothy J Stuhlmiller, Adriana S Beltran, Jose F Olivares-Quintero, Darshan Singh, Noah Sciaky, Joel S Parker, Naim U Rashid, Xin Chen, James S Duncan, Martin C Whittle, Steven P Angus, Sara Hanna Velarde, Brian T Golitz, Xiaping He, Charlene Santos, David B Darr, Kristalyn Gallagher, Lee M Graves, Charles M Perou, Lisa A Carey, H Shelton Earp, Gary L Johnson
Targeting the dysregulated BRAF-MEK-ERK pathway in cancer has increasingly emerged in clinical trial design. Despite clinical responses in specific cancers using inhibitors targeting BRAF and MEK, resistance develops often involving nongenomic adaptive bypass mechanisms. Inhibition of MEK1/2 by trametinib in patients with triple-negative breast cancer (TNBC) induced dramatic transcriptional responses, including upregulation of receptor tyrosine kinases (RTK) comparing tumor samples before and after one week of treatment...
March 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28073847/identification-of-ccr2-and-cd180-as-robust-pharmacodynamic-tumor-and-blood-biomarkers-for-clinical-use-with-brd4-bet-inhibitors
#14
Tammie C Yeh, Greg O'Connor, Philip Petteruti, Austin Dulak, Maureen Hattersley, J Carl Barrett, Huawei Chen
PURPOSE: AZD5153 is a novel BRD4/BET inhibitor with a distinctive bivalent bromodomain binding mode. To support its clinical development, we identified pharmacodynamic (PD) biomarkers for use in clinical trials to establish target engagement. EXPERIMENTAL DESIGN: CCR2 and CD180 mRNAs, initially identified from whole transcriptome profiling, were further evaluated by quantitative PCR in hematologic cell lines, xenografts, and whole blood from rat, healthy volunteers, and patients with cancer...
January 10, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28062857/positive-feedback-loop-mediated-by-protein-phosphatase-1%C3%AE-mobilization-of-p-tefb-and-basal-cdk1-drives-androgen-receptor-in-prostate-cancer
#15
Xiaming Liu, Yanfei Gao, HuiHui Ye, Sean Gerrin, Fen Ma, Yiming Wu, Tengfei Zhang, Joshua Russo, Changmeng Cai, Xin Yuan, Jihong Liu, Shaoyong Chen, Steven P Balk
P-TEFb (CDK9/cyclin T) plays a central role in androgen receptor (AR)-mediated transactivation by phosphorylating both RNA polymerase 2 complex proteins and AR at S81. CDK9 dephosphorylation mobilizes P-TEFb from an inhibitory 7SK ribonucleoprotein complex, but mechanisms targeting phosphatases to P-TEFb are unclear. We show that AR recruits protein phosphatase 1α (PP1α), resulting in P-TEFb mobilization and CDK9-mediated AR S81 phosphorylation. This increased pS81 enhances p300 recruitment, histone acetylation, BRD4 binding and subsequent further recruitment of P-TEFb, generating a positive feedback loop that sustains transcription...
January 6, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28062533/bet-bromodomain-proteins-as-cancer-therapeutic-targets
#16
Shaokun Shu, Kornelia Polyak
Epigenetic regulators are emerging therapeutic targets in a wide variety of human cancers. BET bromodomain proteins have been identified as key regulators of oncogenic transcription factors including MYC; therefore, their inhibition might provide a way to block these "undruggable" targets. Several BET bromodomain inhibitors are in clinical development with promising preliminary findings. However, tumors acquire resistance to these agents in several different ways. In this review, we summarize the role that BET bromodomain proteins play in tumorigenesis as well as the molecular mechanisms underlying therapeutic responses and resistance to their inhibition with emphasis on BRD4 and breast cancer...
January 6, 2017: Cold Spring Harbor Symposia on Quantitative Biology
https://www.readbyqxmd.com/read/27903272/inhibition-of-bromodomain-and-extra-terminal-bet-proteins-increases-nkg2d-ligand-mica-expression-and-sensitivity-to-nk-cell-mediated-cytotoxicity-in-multiple-myeloma-cells-role-of-cmyc-irf4-mir-125b-interplay
#17
Maria Pia Abruzzese, Maria Teresa Bilotta, Cinzia Fionda, Alessandra Zingoni, Alessandra Soriani, Elisabetta Vulpis, Cristiana Borrelli, Beatrice Zitti, Maria Teresa Petrucci, Maria Rosaria Ricciardi, Rosa Molfetta, Rossella Paolini, Angela Santoni, Marco Cippitelli
BACKGROUND: Anti-cancer immune responses may contribute to the control of tumors after conventional chemotherapy, and different observations have indicated that chemotherapeutic agents can induce immune responses resulting in cancer cell death and immune-stimulatory side effects. Increasing experimental and clinical evidence highlight the importance of natural killer (NK) cells in immune responses toward multiple myeloma (MM), and combination therapies able to enhance the activity of NK cells against MM are showing promise in treating this hematologic cancer...
December 1, 2016: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/27858214/synthesis-and-biological-evaluation-of-n-3-oxo-3-4-dihydro-2h-benzo-b-1-4-oxazin-7-yl-benzenesulfonamide-derivatives-as-new-bet-bromodomain-inhibitors-for-anti-hematologic-malignancies-activities
#18
Li Liu, Yongxia Zhu, Zhihao Liu, Tinghong Ye, Weiqiong Zuo, Cuiting Peng, Kunjie Xiao, Ningyu Wang, Luoting Yu
The bromodomain and extra-terminal proteins (BETs), in particular BRD4, has been reported to play important roles in cancer, inflammation, obesity, cardiovascular disease, and neurological disorders. In this paper, a series of benzomorpholinone derivatives were synthesized and biologically evaluated as BETs inhibitors. Detailed structure-activity relationship studies led to the discovery of several new potent compounds, of which 15h and 15i displayed [Formula: see text] values of 2.8 and 4.5 [Formula: see text] against BRD4 (D1), respectively, and showed good anti-proliferation activities against four hematologic malignancies cell lines at low-micromolar concentrations, including MV4-11, OCI-LY10, Pfeifer, and Su-DHL-6 cells...
February 2017: Molecular Diversity
https://www.readbyqxmd.com/read/27846385/an-unexpected-chink-in-the-transcriptional-armor-of-plasmacytoid-dendritic-neoplasms
#19
Maria Kleppe, Ross L Levine
In this issue of Cancer Cell, Ceribelli et al. use functional genomic and chemical screening to reveal the existence of a TCF4/BRD4-dependent oncogenic regulatory network in blastic plasmacytoid dendritic cell neoplasm (BPDCN) and demonstrate that BPDCN cells are highly sensitive to therapeutic targeting of this novel dependency.
November 14, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27827996/the-bromodomain-and-extra-terminal-domain-bet-family-functional-anatomy-of-bet-paralogous-proteins
#20
REVIEW
Yasushi Taniguchi
The Bromodomain and Extra-Terminal Domain (BET) family of proteins is characterized by the presence of two tandem bromodomains and an extra-terminal domain. The mammalian BET family of proteins comprises BRD2, BRD3, BRD4, and BRDT, which are encoded by paralogous genes that may have been generated by repeated duplication of an ancestral gene during evolution. Bromodomains that can specifically bind acetylated lysine residues in histones serve as chromatin-targeting modules that decipher the histone acetylation code...
November 7, 2016: International Journal of Molecular Sciences
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