DOCSLIB.ORG

Chemogenomics for Drug Discovery: Clinical Molecules from Open Access Chemical Probes Cite This: RSC Chem

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Chemogenomics for Drug Discovery: Clinical Molecules from Open Access Chemical Probes Cite This: RSC Chem RSC Chemical Biology View Article Online REVIEW View Journal | View Issue Chemogenomics for drug discovery: clinical molecules from open access chemical probes Cite this: RSC Chem. Biol., 2021, 2, 759 Robert B. A. Quinlan a and Paul E. Brennan *ab In recent years chemical probes have proved valuable tools for the validation of disease-modifying targets, facilitating investigation of target function, safety, and translation. Whilst probes and drugs often differ in their properties, there is a belief that chemical probes are useful for translational studies and can Received 27th January 2021, accelerate the drug discovery process by providing a starting point for small molecule drugs. This review Accepted 25th March 2021 seeks to describe clinical candidates that have been inspired by, or derived from, chemical probes, and DOI: 10.1039/d1cb00016k the process behind their development. By focusing primarily on examples of probes developed by the Structural Genomics Consortium, we examine a variety of epigenetic modulators along with other rsc.li/rsc-chembio classes of probe. Creative Commons Attribution 3.0 Unported Licence. Introduction catalysis.1–5 We have begun to better characterise the extra- catalytic roles of proteins and how these contribute to disease Progress in the understanding of cellular and disease biology pathology, whether as readers of epigenetic marks, as molecular has advanced our knowledge of protein function beyond solely chaperones, or scaffolding proteins. To that end, non-destructive means of target validation and investigation are useful to examine the precise role of a protein in a cellular process. a Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Where the use of RNA inhibition (RNAi) or CRISPR gene editing Old Road Campus, Oxford OX3 7FZ, UK. E-mail: [email protected] b Alzheimer’s Research (UK) Oxford Drug Discovery Institute, Nuffield Department of precludes this, chemical probes are an invaluable tool for rapid This article is licensed under a 6–8 Medicine, University of Oxford, Oxford, OX3 7FZ, UK onset, reversible, and domain specific protein inhibition. Open Access Article. Published on 26 March 2021. Downloaded 10/4/2021 1:16:57 PM. Robert Quinlan completed his Paul Brennan received his PhD MChem in Medicinal and Bio- in organic chemistry from the logical Chemistry (2016) at the University of California, Berkeley University of Edinburgh, during under the mentorship of Paul whichhespenttimeinthelabsof Bartlett working on synthetic Dr Nicolas Blanchard (Universite´ methodology for combinatorial de Strasbourg) and Professor Guy chemistry and synthesizing Lloyd-Jones FRS FRSE. He then inhibitors for new anti-bacterial joined the Synthesis for Biology targets. Following post-doctoral and Medicine Centre for Doctoral research with Steve Ley at Cam- Training (SBM CDT) at the bridge University, Paul returned University of Oxford. He began his to California to take a position at Robert B. A. Quinlan DPhil studies under the supervision Paul E. Brennan Amgen. After two years at Amgen, of Professor Paul Brennan in 2017, Paul accepted a position as working on the development of small molecule epigenetic modulators medicinal chemistry design lead at Pfizer in Sandwich, UK. In for the treatment of neurodegenerative diseases. 2011 Paul joined the Structural Genomics Consortium at the University of Oxford, before becoming Professor of Medicinal Chemistry for the Centre for Medicines Discovery and head of chemistry of the Alzheimer’s Research UK Oxford Drug Discovery Institute. His research is focused on drug discovery for dementia and on finding small molecule chemical probes for unexplored protein families. © 2021 The Author(s). Published by the Royal Society of Chemistry RSC Chem. Biol., 2021, 2, 759–795 | 759 View Article Online Review RSC Chemical Biology They permit the evaluation of a particular role a protein plays, drug-likeness with drugs distributed around a score of one, and whilst leaving other interactions intact. In combination with non-drugs at zero.14 techniques such as RNAi, they paint a complete picture of a protein’s role within a cell.7 Chemical probes are defined by four main criteria:6,9,10 BET bromodomains 1. A minimal in vitro potency of less than 100 nM. 2. Greater than 30-fold selectivity over sequence-related proteins. Bromodomains (BRDs) are a class of epigenetic reader domains 15 3. Profiled against an industry standard selection of pharmaco- that recognise acetylated lysine (KAc) residues, a reversible logically relevant targets. post-translational modification with a key role in regulating 16 4. On-target cellular effects at greater than 1 mM. transcription. A subset of BRDs have also been shown to recognise 17,18 Their utility in interrogating the function of a protein and propionylated, butyrylated, and crotonylated lysines, demon- thus its relevance11 as a drug target has led a consortium of strating the importance of these domains in interpreting the industrial and academic researchers to establish a collaboration chromatin landscape. Evolutionarily conserved, they form part 19 for the development of probes for the entire proteome.12 Target of diverse nuclear proteins and complexes. The bromo- and 2035 aims to translate the advances made in genomics13 to extra C-terminal (BET) subfamily of bromodomains is perhaps 4,20,21 advances in the clinic, specifically new small-molecules for the the best studied and validated in a disease context. Its treatment of disease. One advantage of chemical probes often members (BRD2, BRD3, BRD4, and BRDT) have been implicated touted is that they are more likely to mimic the pharmacology of in a variety of disease processes, including cancer, viral infection, 22–25 a drug.7 Whilst not designed with drug-like characteristics in and inflammation. mind (for example absorption, distribution, metabolism, and excretion (ADME) properties),7 there is nevertheless a belief that The probe: (+)-JQ1 probes can provide a small-molecule starting point to accelerate Disclosed just months apart, the first pan-BET inhibitors (+)-JQ126 27 Creative Commons Attribution 3.0 Unported Licence. the drug discovery process. In this review, we highlight some and I-BET762 (Fig. 1) represented key milestones in the targeting small-molecule chemical probes that have both inspired and of BET proteins. Inspired by a triazolothienodiazepine scaffold mirrored clinical candidates, with a focus on epigenetic modulators. patented in 2009,28 (+)-JQ1 was developed following molecular We describe the target and development of the probe itself, the modelling of potential ligands against the bromodomain of BRD4. medicinal chemistry optimisation that led to the eventual clinical It was a potent inhibitor of both bromodomains of BRD4 candidate. We also include an estimate of the relative drug-likeness (KD(BRD4(1)) = 50 nM, KD(BRD4(2)) = 90 nM by isothermal of each compound calculated using the Molsoft drug-likness and titration calorimetry (ITC)), with similar potency against both molecular property prediction tool. A higher score indicates greater bromodomains of BRD3. It showed approximately three-fold This article is licensed under a Open Access Article. Published on 26 March 2021. Downloaded 10/4/2021 1:16:57 PM. Fig. 1 Chemical probe (+)-JQ1 and structurally derived clinical candidates: I-BET762, OTX015,andCPI-0610. Their potency against relevant BET bromodomains is presented, along with pharmacokinetic (PK) data where available, and their clinical status. Also included is a relative drug-likeness score to highlight the changes in drug-likeness moving from probe to drug. a PO = per os, by mouth. b QD = quaque die, once daily. c Assume 70 kg bodyweight for humans. 760 | RSC Chem. Biol., 2021, 2, 759–795 © 2021 The Author(s). Published by the Royal Society of Chemistry View Article Online RSC Chemical Biology Review weaker binding against BRD2 and BRDT. Pan-BET inhibition assays and was selective against other representative bromo- using (+)-JQ1 has shown anti-proliferative effects against a domains. It induced growth inhibition in in vivo models of multitude of haematological and solid malignancies, including nuclear protein in testis (NUT) midline carcinoma,44 MM,45 and breast,29,30 colorectal,31 and brain cancers,32,33 as well as multiple prostate cancer.46 In 2012, I-BET762 was advanced to the clinic myeloma (MM),34,35 leukaemia,36–38 and lymphoma.35,38,39 (+)-JQ1 for the treatment of NUT carcinoma and other solid tumours.44 was key to establishing the mechanistic significance of BET Target engagement was observed with once-daily dosing, with inhibition, however was unsuitable for clinical progression due several patients experiencing clinical benefit. Despite that, I-BET762 26 to its short half-life and thus its required dose concentrations showed rapid elimination (t1/2 = 3–7 hours) and transient responses, being above tolerable levels in vivo.40 thought to be due to the activation of resistance mechanisms to I-BET762/GSK525762/molibresib. I-BET762 was identified BET inhibition. Nevertheless, it is currently under clinical inves- following a screen of compounds that upregulated the Apoli- tigation for the treatment of acute myeloid leukaemia (AML) poprotein A1 (ApoA1) gene as a proxy for BET inhibition,27 (NCT01943851), with manageable adverse events and some objective leading to the identification of an initial hit (Fig. 2, 1) with an responses observed.47 It is also being evaluated as part of a 41 EC50 of 440 nM for the induction of
Load more

Recommended publications
  • Triazolobenzodiazepines and -Triazepines As Protein Interaction Inhibitors Targeting Bromodomains of the BET Family
    Dissertation zur Erlangung des Doktorgrades der Fakultät für Chemie und Pharmazie der Ludwig-Maximilians-Universität München Triazolobenzodiazepines and -triazepines as Protein Interaction Inhibitors Targeting Bromodomains of the BET Family Matthias Alfons Wrobel aus Weiden i.d.OPf. 2013 Erklärung Diese Dissertation wurde im Sinne von § 7 der Promotionsordnung vom 28. November 2011 von Herrn Prof. Dr. Franz Bracher betreut. Eidesstattliche Versicherung Diese Dissertation wurde eigenständig und ohne unerlaubte Hilfe erarbeitet. München, 09.12.2013 Matthias Wrobel Dissertation eingereicht am 10.12.2013 1. Gutachter: Prof. Dr. Franz Bracher 2. Gutachter: Prof. Dr. Stefan Knapp Mündliche Prüfung am 21.01.2014 This dissertation was carried out in close collaboration with the Structural Genomics Consortium of the University of Oxford. Prof. Dr. Stefan Knapp Dr. Panagis Filippakopoulos Screening via DSF / ITC / Co-crystallization …für Caro …für meine Familie Acknowledgements I would like to thank Prof. Dr. Franz Bracher for giving me the possibility to work on this interesting topic, the helpful advices in meetings, always having a sympathetic ear for all kind of affairs and his support during the time of my PhD Thesis. I would also like to thank all the members of the Board of Examiners. In gratitude for the opportunity to visit his group at the University of Oxford (UK) and his considerable commitment for our collaboration, I would like to thank Prof. Dr. Stefan Knapp. Special thanks goes to Dr. Panagis Filippakopoulos for his supervision during my stays at the SGC and his patience and support in uncountable discussions about co-crystallization, structure optimization and critical appraisal of screening results.
    [Show full text]
  • BET Bromodomain Protein Inhibition Is a Therapeutic Option for Medulloblastoma
    www.impactjournals.com/oncotarget/ Oncotarget, November, Vol.4, No 11 BET bromodomain protein inhibition is a therapeutic option for medulloblastoma Anton Henssen1, Theresa Thor2,4, Andrea Odersky 1, Lukas Heukamp6, Nicolai El- Hindy7, Anneleen Beckers8, Frank Speleman8, Kristina Althoff1, Simon Schäfers1, Alexander Schramm1, Ulrich Sure7, Gudrun Fleischhack1, Angelika Eggert9, Johannes H. Schulte1,5 1 Department of Pediatric Oncology and Hematology, University Children`s Hospital Essen, Essen, Germany 2 German Cancer Consortium (DKTK), Germany 3 Translational Neuro-Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany 4 German Cancer Research Center (DKFZ), Heidelberg, Germany 5 Centre for Medical Biotechnology, University Duisburg-Essen, Essen, Germany 6 Institute of Pathology, University Hospital Cologne, Cologne, Germany 7 Department of Neurosurgery, University of Essen, Essen, Germany 8 Center of Medical Genetics Ghent (CMGG), Ghent University Hospital, Ghent, Belgium 9 Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Germany Correspondence to: Johannes H. Schulte, email: [email protected] Keywords: BET bromodomains, BRD4, MYC, JQ1, pediatric brain tumors, targeted therapy Received: October 23, 2013 Accepted: October 25, 2013 Published: October 27, 2013 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT: Medulloblastoma is the most common malignant brain tumor of childhood, and represents a significant clinical challenge in pediatric oncology, since overall survival currently remains under 70%. Patients with tumors overexpressing MYC or harboring a MYC oncogene amplification have an extremely poor prognosis. Pharmacologically inhibiting MYC expression may, thus, have clinical utility given its pathogenetic role in medulloblastoma.
    [Show full text]
  • Macrophage Inflammatory Responses BET Inhibitor JQ1 Impair Mouse
    BET Protein Function Is Required for Inflammation: Brd2 Genetic Disruption and BET Inhibitor JQ1 Impair Mouse Macrophage Inflammatory Responses This information is current as of October 4, 2021. Anna C. Belkina, Barbara S. Nikolajczyk and Gerald V. Denis J Immunol 2013; 190:3670-3678; Prepublished online 18 February 2013; doi: 10.4049/jimmunol.1202838 Downloaded from http://www.jimmunol.org/content/190/7/3670 Supplementary http://www.jimmunol.org/content/suppl/2013/02/19/jimmunol.120283 Material 8.DC1 http://www.jimmunol.org/ References This article cites 51 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/190/7/3670.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on October 4, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology BET Protein Function Is Required for Inflammation: Brd2 Genetic Disruption and BET Inhibitor JQ1 Impair Mouse Macrophage Inflammatory Responses Anna C.
    [Show full text]
  • A Phase IB Dose Exploration Trial with MK-8628, a Small
    Official Protocol Title: A Phase IB Dose Exploration Trial with MK-8628, a Small Molecule Inhibitor of the Bromodomain and Extra-Terminal (BET) Proteins, in Subjects with Selected Advanced Solid Tumors NCT number: NCT02698176 Document Date: 21-Nov-2016 Product: MK-8628 1 Protocol/Amendment No.: 006-02 THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., WHITEHOUSE STATION, NJ, U.S.A. SPONSOR: Oncoethix GmbH, a wholly owned subsidiary of Merck Sharp & Dohme Corp. (hereafter referred to as the Sponsor or Merck) Weystrasse 20 6000 Lucerne Switzerland Protocol-specific Sponsor Contact information can be found in the Investigator Trial File Binder (or equivalent). TITLE: A Phase IB Dose Exploration Trial with MK-8628, a Small Molecule Inhibitor of the Bromodomain and Extra-Terminal (BET) Proteins, in Subjects with Selected Advanced Solid Tumors IND NUMBER: 123,715 EudraCT NUMBER: 2015-005488-18 MK-8628-006-02 Final Protocol 21-Nov-2016 Confidential Product: MK-8628 2 Protocol/Amendment No.: 006-02 TABLE OF CONTENTS SUMMARY OF CHANGES................................................................................................ 11 1.0 TRIAL SUMMARY.................................................................................................. 13 2.0 TRIAL DESIGN........................................................................................................ 14 2.1 Trial Design ..........................................................................................................
    [Show full text]
  • Targeting MYC Dependence in Cancer by Inhibiting BET Bromodomains
    Targeting MYC dependence in cancer by inhibiting BET bromodomains Jennifer A. Mertz1, Andrew R. Conery1, Barbara M. Bryant, Peter Sandy, Srividya Balasubramanian, Deanna A. Mele, Louise Bergeron, and Robert J. Sims III2 Constellation Pharmaceuticals, Inc., Cambridge, MA 02142 Edited* by Robert N. Eisenman, Fred Hutchinson Cancer Research Center, Seattle, WA, and approved August 30, 2011 (received for review May 23, 2011) The MYC transcription factor is a master regulator of diverse in preclinical animal models of endotoxic shock caused by acti- cellular functions and has been long considered a compelling vation of Toll-like receptors that trigger the up-regulation of therapeutic target because of its role in a range of human cytokines controlled by NF-κB (7). Importantly, although RNAi- malignancies. However, pharmacologic inhibition of MYC function mediated depletion of any one individual BET protein has broad has proven challenging because of both the diverse mechanisms effects on transcription, pharmacologic inhibition of the BET driving its aberrant expression and the challenge of disrupting bromodomains perturbs the transcription of a narrower range protein–DNA interactions. Here, we demonstrate the rapid and po- of genes (7). These findings suggest an opportunity to use BET- tent abrogation of MYC gene transcription by representative small bromodomain inhibitors to fine-tune key regulatory pathways for molecule inhibitors of the BET family of chromatin adaptors. MYC therapeutic benefit. transcriptional suppression was observed in the context of the nat- BET inhibitors exhibit anticancer effects in both in vitro and ural, chromosomally translocated, and amplified gene locus. Inhi- in vivo models of midline carcinoma (8), a rare but lethal disease bition of BET bromodomain–promoter interactions and subsequent that frequently harbors a chromosomal translocation in which reduction of MYC transcript and protein levels resulted in G1 arrest the bromodomains of BRD4 are fused to the NUT gene (9).
    [Show full text]
  • Part 1: Design and Synthesis of BRDT Selective Inhibitors As Male
    Part 1: Design and Synthesis of BRDT Selective Inhibitors as Male Contraceptive Agents Part 2: Focused Library Synthesis for TGR5 (Takeda G Protein-Coupled Receptor 5) Antagonist A Dissertation SUBMITTED TO THE FACULTY OF UNIVERSITY OF MINNESOTA BY Jiewei Jiang IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY Dr. Gunda I. Georg September 2020 ©2020 Jiewei Jiang All Rights Reserved Acknowledgements I would like to express my sincere gratitude to my advisor Dr. Gunda Georg for her mentorship and guidance over the six years. Without her continuous support, I could not have accomplished this journey. Her dedication and enthusiasm to science will always be inspiring me in my future career. My appreciation also goes to Dr. Elizabeth Ambrose, Dr. Carrie Haskell-Luevano, and Dr. William Pomerantz for serving as my committee members. Their insightful suggestions as well as helpful critiques made me become a better scientific researcher. I am deeply grateful to people who made my work herein possible. Thank you to Dr. Timothy Ward and Dr. Peiliang Zhao for their contribution in the synthesis; Dr. Jon Hawkinson, Jonathan Solberg, Dr. Carolyn Paulson, Xianghong Guan for their expertise with fluorescence polarization assay; Dr. Jun Qi and Nana K. Offei-Addo for their expertise with AlphaScreen assay; Dr. Ernst Schönbrunn and Dr. Alice Chan for elegant co-crystal structures; Kristen John for her efforts and discussions about the TGR5 screening. I would like to thank all the Georg group and ITDD members for not only showing me how to do science but also making my everyday life colorful.
    [Show full text]
  • UCSF UC San Francisco Electronic Theses and Dissertations
    UCSF UC San Francisco Electronic Theses and Dissertations Title Deep phenotypic profiling of neuroactive drugs in larval zebrafish Permalink https://escholarship.org/uc/item/3vk1d0gr Author Gendelev, Leo Publication Date 2019 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California Deep phenotypic profiling of neuro-active drugs in larval Zebrafish by Lev Gendelev DISSERTATION Submitted in partial satisfaction of the requirements for degree of DOCTOR OF PHILOSOPHY in Biophysics in the GRADUATE DIVISION of the UNIVERSITY OF CALIFORNIA, SAN FRANCISCO Approved: ______________________________________________________________________________Michael Keiser Chair ______________________________________________________________________________DAVID KOKEL ______________________________________________________________________________Jim Wells ______________________________________________________________________________ ______________________________________________________________________________ Committee Members Copyright 2019 by Lev (Leo) Gendelev ii In Loving Memory of My Mother, Lucy Gendelev iii Acknowledgements First of all, I thank my advisor, Michael Keiser, for his unwavering support through the most difficult of times. I will above all else reminisce over our brainstorming sessions, where my half- wrought white-board scribbles were met with enthusiasm and sometimes even developed into exciting side-projects. My PhD experience felt less like work and more like a fantastical scientific
    [Show full text]
  • BET Protein Inhibitor JQ1 Downregulates Chromatin
    Zhou et al. Oncogenesis (2020) 9:33 https://doi.org/10.1038/s41389-020-0218-z Oncogenesis ARTICLE Open Access BET protein inhibitor JQ1 downregulates chromatin accessibility and suppresses metastasis of gastric cancer via inactivating RUNX2/NID1 signaling Siqi Zhou1,2, Shu Zhang2,3,LeiWang2,3, Shuling Huang2,3,YueYuan1,2,JieYang1,2,HuiWang2,3, Xihan Li2,3,PinWang2,3, Lin Zhou2,3,JunYang4,YuemeiXu4,HuanGao5, Yixuan Zhang2,3,YingLv2,3 and Xiaoping Zou1,2 Abstract Chromatin accessibility is critical for tumor development, whose mechanisms remain unclear. As a crucial regulator for chromatin remodeling, BRD4 promotes tumor progression by regulating multiple genes. As a small-molecule inhibitor of BRD4, JQ1 has potent chemotherapeutic activity against various human cancers. However, whether JQ1 has potential anti-tumor effects and how JQ1 regulates global transcription in gastric cancer (GC) remain largely unknown. In this research, we found BRD4 was highly expressed in GC tissues and was significantly associated with poor prognosis. JQ1 inhibited the proliferation and induced apoptosis of GC cells in vitro. Besides, JQ1 suppressed the migration and invasion of cancer cells by inducing MET. Notably, an assay for transposase-accessible chromatin using sequencing (ATAC-seq) data showed that JQ1 obviously downregulated the chromatin accessibility of GC cells and differentially accessible regions were highly enriched for RUNX2-binding motifs. Combinational analysis of ATAC-seq and RNA-seq 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; data discovered NID1 as the downstream target of JQ1 and JQ1 reduced NID1 expression in GC cells. Chromatin immunoprecipitation, luciferase reporter gene assay, and rescue experiments all confirmed that RUNX2/NID1 axis was responsible for JQ1-inhibiting metastasis of GC cells.
    [Show full text]
  • Macrophage Inflammatory Responses BET
    BET Protein Function Is Required for Inflammation: Brd2 Genetic Disruption and BET Inhibitor JQ1 Impair Mouse Macrophage Inflammatory Responses This information is current as of October 2, 2021. Anna C. Belkina, Barbara S. Nikolajczyk and Gerald V. Denis J Immunol 2013; 190:3670-3678; Prepublished online 18 February 2013; doi: 10.4049/jimmunol.1202838 Downloaded from http://www.jimmunol.org/content/190/7/3670 Supplementary http://www.jimmunol.org/content/suppl/2013/02/19/jimmunol.120283 Material 8.DC1 http://www.jimmunol.org/ References This article cites 51 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/190/7/3670.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on October 2, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology BET Protein Function Is Required for Inflammation: Brd2 Genetic Disruption and BET Inhibitor JQ1 Impair Mouse Macrophage Inflammatory Responses Anna C.
    [Show full text]
  • Bromodomain Inhibitors in Degenerative Eye Disease; an Alternative to VEGF Inhibitors in Macular Degeneration?
    ISSN: 2641-6360 DOI: 10.33552/WJOVR.2020.03.000553 World Journal of Ophthalmology & Vision Research Short Communication Copyright © All rights are reserved by Joseph W Eichenbaum Bromodomain Inhibitors in Degenerative Eye Disease; An Alternative to VEGF Inhibitors in Macular Degeneration? Joseph W Eichenbaum* Adjunct Associate Professor of Ophthalmology and Pharmacology, Icahn School of Medicine, USA *Corresponding author: Received Date: December 24, 2019 Published Date: January 10, 2020 Joseph W Eichenbaum, Adjunct Associate Professor of Ophthalmology and Pharmacology, Icahn School of Medicine, Mount Sinai, USA. Abstract For over a decade VEGF (Vascular Endothelial Growth Factor) inhibitors have been the definitive treatment of choroidal neovascularization associated with adult onset macular degeneration. While the induction of “wet macular degeneration” treatment requires 2-3 intravitreal injections, over 2-3 months, the maintenance phase for sustained good visual acuity may be 6 injections or more per year, protracted over 6-8 years. Unfortunately, this treatment, even if the extended number and time of intravitreal injections could be packaged in a sustained delivery device, would still not represent a cure. Alternatively, if the treatment could be targeted to genetic, oxidative stress, inflammatory and immune modification from Bromodomain inhibitors (BRD I), (which would work through these transcription factors from an early stage to correct these macular problems), then patients might be given a more direct and shorter intervention with perhaps oral maintenance as necessary. Similar consideration for BRD I Keywords:may be developed for uveitis, corneal scarring and retinal ganglion cell protection. Macular degeneration; VEGF Inhibitors; Bromodomain inhibitors; Uveitis; Corneal scarring; RGC (Retinal Fanglion Cell) protection Introduction Development of the optimal treatment for the majority [1].
    [Show full text]
  • The Bromodomain BET Inhibitor JQ1 Suppresses Tumor Angiogenesis in Models of Childhood Sarcoma Hemant K
    Published OnlineFirst February 23, 2016; DOI: 10.1158/1535-7163.MCT-15-0567 Cancer Biology and Signal Transduction Molecular Cancer Therapeutics The Bromodomain BET Inhibitor JQ1 Suppresses Tumor Angiogenesis in Models of Childhood Sarcoma Hemant K. Bid1, Doris A. Phelps1, Linlin Xaio1, Denis C. Guttridge2, Jiayuh Lin1, Cheryl London3, Laurence H. Baker4, Xiaokui Mo5, and Peter J. Houghton1,6 Abstract The bromodomain and extra-terminal domain inhibitor similar sensitivity in vivo as xenografts. Further investigation JQ1 has marked antitumor activity against several hematologic showed that JQ1 reduced tumor vascularization. This was malignanciesaswellassolidtumormodels.Here,weinves- secondary to both drug-induced downregulation of tumor- tigated its activity in vitro and in vivo against models of child- derived growth factors and direct effects of JQ1 on vascular hood rhabdomyosarcoma and Ewing sarcoma. In vitro,JQ1 elements. JQ1 suppressed VEGF-stimulated vascularization of (but not the inactive enantiomer JQ1R) inhibited cell prolif- Matrigel plugs in mice, and in vitro suppressed differentiation, eration and increased G1 fraction of cells, although there was proliferation, and invasion of human umbilical cord vascular no correlation between cell line sensitivity and suppression of endothelial cells (HUVEC). In HUVECs, JQ1 partially sup- c-MYC or MYCN. In vivo,xenograftsshowedsignificant inhi- pressed c-MYC levels, but dramatically reduced AP-1 levels bition of growth during the period of treatment, and rapid and activity through suppression of the AP-1–associated pro- regrowth after treatment was stopped, activity typical of anti- tein FOSL1. Our data suggest that the antitumor activity of JQ1 angiogenic agents. Furthermore, xenografts derived from cell in these sarcoma models is largely a consequence of its anti- lines intrinsically resistant or sensitive to JQ1 in vitro had angiogenic activity.
    [Show full text]
  • Update in Pediatric Neuro-Oncology
    bioengineering Update in Pediatric Neuro-Oncology Edited by Soumen Khatua and Natasha Pillay Smiley Printed Edition of the Special Issue Published in Bioengineering www.mdpi.com/journal/bioengineering Update in Pediatric Neuro-Oncology Update in Pediatric Neuro-Oncology Special Issue Editors Soumen Khatua Natasha Pillay Smiley MDPI • Basel • Beijing • Wuhan • Barcelona • Belgrade Special Issue Editors Soumen Khatua The University of Texas MD Anderson Cancer Center USA Natasha Pillay Smiley Ann and Robert H. Lurie Children’s Hospital USA Editorial Office MDPI St. Alban-Anlage 66 4052 Basel, Switzerland This is a reprint of articles from the Special Issue published online in the open access journal Bioengineering (ISSN 2306-5354) in 2018 (available at: https://www.mdpi.com/journal/ bioengineering/special issues/pediatr neuro oncol) For citation purposes, cite each article independently as indicated on the article page online and as indicated below: LastName, A.A.; LastName, B.B.; LastName, C.C. Article Title. Journal Name Year, Article Number, Page Range. ISBN 978-3-03897-539-7 (Pbk) ISBN 978-3-03897-540-3 (PDF) Cover image courtesy of Natasha Pillay Smiley. c 2019 by the authors. Articles in this book are Open Access and distributed under the Creative Commons Attribution (CC BY) license, which allows users to download, copy and build upon published articles, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. The book as a whole is distributed by MDPI under the terms and conditions of the Creative Commons license CC BY-NC-ND. Contents About the Special Issue Editors ....................................
    [Show full text]