DOCSLIB.ORG

DCTD Program Accomplishments

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
DCTD Program Accomplishments Institute Cancer National Division of Cancer Treatment and Diagnosis Program Accomplishments 2008 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health Institute Cancer National Division of Cancer Treatment and Diagnosis Program Accomplishments 2008 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health Table of Contents Foreword 4 Division of Cancer Treatment and Diagnosis 6 Overview 7 DCTD Management 10 DCTD Research Grants 11 Major Ongoing Initiatives and Accomplishments 12 Cancer Diagnosis Program 16 Overview 17 Major Ongoing Initiatives 17 Current Funding Opportunities 22 Partnerships and Collaborations 24 Scientific Advances 26 Tools, Products, and Resources 27 Cancer Imaging Program 30 Overview 31 Major Ongoing Initiatives 31 Current Funding Opportunities 45 Partnerships and Collaborations 48 Scientific Advances 53 Tools, Products, and Resources 55 Cancer Therapy Evaluation Program 58 Overview 59 Major Ongoing Initiatives 59 Significant Ongoing Trials 65 Current Funding Opportunities 71 Partnerships and Collaborations 73 Scientific Advances 75 Tools, Products, and Resources 77 2 Division of Cancer Treatment and Diagnosis Developmental Therapeutics Program 80 Overview 81 Major Ongoing Initiatives 83 Tools, Products, and Resources 87 Scientific Advances 94 Radiation Research Program 96 Overview 97 Partnerships and Collaborations 99 Scientific Advances 104 Tools, Products, and Resources 106 Meetings and Workshops 107 Biometric Research Branch 108 Overview 109 Partnerships and Collaborations 109 Scientific Advances 114 Tools, Products, and Resources 120 Office of Cancer Complementary and Alternative Medicine 122 Overview 123 Selected Funded Projects 123 Current Funding Opportunity 126 Partnerships and Collaborations 127 Tools, Products, and Resources 127 Appendix: DCTD Staff Roster 129 Program Accomplishments 2008 3 Foreword The Division of Cancer Treatment and Diagnosis (DCTD) focuses its activities on developing novel diagnostics and therapies for cancer. DCTD staff members, along with colleagues throughout the National Cancer Institute (NCI), academia, and industry, are working together to generate a seamless pipeline of biomarkers and therapeutics that runs the gamut from initial efforts in discovery through late­stage clinical trials. New cancer imaging techniques play a critical role in support of this pipeline as advances in image­guided diagnosis and image­guided therapies continue to emerge. A primary goal of NCI’s DCTD is to decrease the time necessary to bring anticancer drugs and biomarkers to the clinic while enhancing our ability to predict which treatments will be most useful for each patient. At the core of this objective is the implementation of the recommendations of the Clinical Trials Working Group (CTWG) and the Translational Research Working Group (TRWG), new efforts to coordinate and enhance NCI’s drug discovery and chemical­biology engines, and our continued emphasis on first­in­human clinical trials. Furthermore, DCTD has recently completed a process in which unmet research needs in cancer therapeutics and diagnostics have been evaluated. The box accompanying this message provides a summary of these areas of investigative interest for the coming year. Under the auspices of the CTWG, which in 2005 recommended 22 strategic initiatives for revamping the institute’s cancer clinical trials system, NCI has conducted a systematic review of the steps involved in opening a clinical trial. On average, it takes about 1,000 days for an NCI­supported clinical trial to move from inception within a cooperative group to activation in an NCI­designated cancer center. As a result of these findings, NCI Director John Niederhuber, M.D., has pledged to cut the time from inception to activation in half. Although NCI has a robust program of clinical trials and later stage preclinical development, over the past 15 years its drug discovery efforts have received less attention. To bridge the gap between academic drug discovery and the develop­ ment of anticancer agents in the clinic, NCI is in the process of reinvigorating the process of cancer drug discovery through which academia, the private sector, and government work together to enhance NCI’s capability to move novel compounds through the entire pathway from synthesis and lead molecule optimization, to target qualification, pharmacology, toxicology, formulation, and first­in­human trials. In addition to the development of small molecule anticancer agents, DCTD is working to improve the range of immunotherapeutic approaches to cancer Dr. James H. Doroshow, treatment. During a DCTD workshop conducted in July 2007 (http://web. Director, NCI Division of ncifcrf.gov/research/brb/workshops/NCI%20Immunotherapy%20Workshop% Cancer Treatment and Diagnosis 207­12­07.pdf), the immunotherapeutic molecules in the NCI pipeline were evaluated. Workshop participants produced a prioritized list of 20 possible immunomodulatory molecules that hold particular promise for use in cancer treatment. An organized process is now in place to either produce or obtain access to these compounds for use in future NCI­supported clinical trials. Results from NCI’s first­ever phase 0 trial—showing that such studies appear to substantially compress the drug development timeline—were presented last year at the annual meeting of the American Society of Clinical Oncology. Several new therapeutic and imaging agents are being readied for additional NCI phase 0 studies in collaboration with the NCI Center for Cancer Research at the NIH Clinical Center. 4 Division of Cancer Treatment and Diagnosis Division of Cancer Treatment and Diagnos is DCTD is also playing an important role in the implementation of recommendations made last year by the TRWG. The TRWG report developed 15 recommendations that focus on “early translation”—work done to move basic research discoveries into phase I and phase II clinical trials. The work of the TRWG complements several CTWG­related activities, which are focused on “late translation,” that is, primarily phase III clinical trials. At the request of Dr. Niederhuber, DCTD is now overseeing the Specialized Programs of Research Excellence (SPOREs), a major NCI vehicle for translational research. The SPOREs will be the chief component of the newly formed Translational Research Program (TRP) in DCTD. In the pages that follow, you will find a summary of recently established priorities and scientific advances made possible by the many gifted and committed staff members throughout the division. DCTD Research Interests Areas of research interest currently underinvestigated • Validation of imaging as a biomarker, including development in the DCTD portfolio: of methods to better determine a response to therapy • Development of new imaging agents Enhancing Tumor Response to Therapy • Development and application of diagnostic devices and • Target­based drug development technologies that support multi­analyte molecular assays • Development of combination therapies in clinically • Development of integrated lab­on­a­chip diagnostic relevant models devices for real­time analysis of biospecimens • Targeting molecular signaling pathways • Methods, mechanisms, and technologies to ensure the • Reducing toxicity using image­guided interventions to availability of clinical specimens for translational research target drug delivery and activation • Studies on the beneficial or harmful effects of anticancer Clinical Studies agents on unintended targets • Translational and clinical studies in the following • Development of approaches, including complementary underinvestigated diseases: pancreatic cancer, squamous medicine approaches, to improve the therapeutic index cell carcinoma of the head and neck, bladder cancer, of standard and investigational anticancer therapies and sarcoma • Validation of the clinical utility of molecular profiles Investigations of the Tumor Microenvironment • Clinical studies using imaging approaches to characterize • Design and testing of agents that target the tumor disease anatomy, physiology, and molecular biology microenvironment using clinically relevant models • Validation of the clinical utility of novel, innovative clinical • Exploiting the tumor microenvironment’s role in therapy diagnostic devices • Understanding the dynamic relationship between • Development of personalized medicine approaches tumors and cells in the microenvironment including the discovery, development, and qualification • Measuring and evaluating the role of the tumor of biomarkers to define efficacy, toxicity, dosing, and microenvironment in tumor transformations through schedule of therapy imaging and other noninvasive methods Further details concerning these areas of research can be Development of New Methods and Technologies found on the DCTD Website: http://dctd.cancer.gov. • Development of new imaging technologies, including novel hardware, new research interfaces, refinement of image processing, and further development of virtual imaging Program Accomplishments 2008 5 Division of Cancer Treatment and Diagnosis Program Accomplishments The Division of Cancer Treatment and Diagnosis (DCTD) collaborates with other National Cancer Institute (NCI) components as the world’s largest sponsor of clinical cancer research. 6 Division of Cancer Treatment and Diagnosis Division of Cancer Treatment and D iagnos is DCTD Overview Cancer Diagnosis Program (CDP) strives to improve the diagnosis and assess­ The multiple programs within DCTD work ment of cancer by effectively
Load more

Recommended publications
  • Marine Natural Products: a Source of Novel Anticancer Drugs
    marine drugs Review Marine Natural Products: A Source of Novel Anticancer Drugs Shaden A. M. Khalifa 1,2, Nizar Elias 3, Mohamed A. Farag 4,5, Lei Chen 6, Aamer Saeed 7 , Mohamed-Elamir F. Hegazy 8,9, Moustafa S. Moustafa 10, Aida Abd El-Wahed 10, Saleh M. Al-Mousawi 10, Syed G. Musharraf 11, Fang-Rong Chang 12 , Arihiro Iwasaki 13 , Kiyotake Suenaga 13 , Muaaz Alajlani 14,15, Ulf Göransson 15 and Hesham R. El-Seedi 15,16,17,18,* 1 Clinical Research Centre, Karolinska University Hospital, Novum, 14157 Huddinge, Stockholm, Sweden 2 Department of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, SE 106 91 Stockholm, Sweden 3 Department of Laboratory Medicine, Faculty of Medicine, University of Kalamoon, P.O. Box 222 Dayr Atiyah, Syria 4 Pharmacognosy Department, College of Pharmacy, Cairo University, Kasr el Aini St., P.B. 11562 Cairo, Egypt 5 Department of Chemistry, School of Sciences & Engineering, The American University in Cairo, 11835 New Cairo, Egypt 6 College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, China 7 Department of Chemitry, Quaid-i-Azam University, Islamabad 45320, Pakistan 8 Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudingerweg 5, 55128 Mainz, Germany 9 Chemistry of Medicinal Plants Department, National Research Centre, 33 El-Bohouth St., Dokki, 12622 Giza, Egypt 10 Department of Chemistry, Faculty of Science, University of Kuwait, 13060 Safat, Kuwait 11 H.E.J. Research Institute of Chemistry,
    [Show full text]
  • Isolation and Identification of Bioactive Secondary Metabolites from Salinispora Arenicola Obtained from Ocean Sediments from the Madeira Archipelago
    Fredilson da Veiga Melo Biochemistry, B. Sc. Isolation and identification of bioactive secondary metabolites from Salinispora arenicola obtained from ocean sediments from the Madeira Archipelago Dissertation for degree of Master in Biochemistry Supervisor: Dr. Susana P. Gaudêncio Assistant Researcher, REQUIMTE, LAQV, Chemistry Department and UCIBIO, Life Science Department – FCT/UNL Co-supervisor: Dr. Florbela Pereira Post-Doc Researcher, REQUIMTE, LAQV, Chemistry Department – FCT/UNL December 2016 Fredilson da Veiga Melo Biochemistry, B. Sc. Isolation and identification of bioactive secondary metabolites from Salinispora arenicola obtained from ocean sediments from the Madeira Archipelago Dissertation for degree of Master in Biochemistry Supervisor: Dr. Susana P. Gaudêncio Assistant Researcher, REQUIMTE, LAQV, Chemistry Department and UCIBIO, Life Science Department – FCT/UNL Co-supervisor: Dr. Florbela Pereira Post-Doc Researcher, REQUIMTE, LAQV, Chemistry Department – FCT/UNL December 2016 Copyright © Fredilson da Veiga Melo, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa The Faculty of Science and Technology and Universidade Nova de Lisboa have the right, forever and without geographical limits, to file and publish this dissertation through printed copies reproduced in paper or digital form, or by any other means known or Be invented, and to disclose it through scientific repositories and to allow its copying and distribution for non-commercial educational or research purposes, provided the author and publisher are credited. i Aknowledgments To my mom for allowing me to pursuit my dream. This is not a repayment, but a token of appreciation for the trust you put on me. To my landlords who have become a second family. To Dr Susana Gaudêncio and Dr Florbela Pereira for taking me in their lab, and for being very understanding and patient.
    [Show full text]
  • WO 2017/223239 Al 28 December 2017 (28.12.2017) W !P O PCT
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2017/223239 Al 28 December 2017 (28.12.2017) W !P O PCT (51) International Patent Classification: Published: A61K 31/445 (2006.01) C07D 471/04 (2006.01) — with international search report (Art. 21(3)) A61K 31/437 {2006.01) — before the expiration of the time limit for amending the (21) International Application Number: claims and to be republished in the event of receipt of PCT/US20 17/038609 amendments (Rule 48.2(h)) (22) International Filing Date: 2 1 June 2017 (21 .06.2017) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 62/352,820 2 1 June 2016 (21 .06.2016) 62/456,526 08 February 2017 (08.02.2017) (71) Applicant: X4 PHARMACEUTICALS, INC. [US/US]; 955 Massachusetts Avenue; 4th Floor, Cambridge, Massa chusetts 02139 (US). (72) Inventors: BOURQUE, Elyse Marie Josee; 3115 Racine Street, Unit 214, Bellingham, Washington 98226 (US). SK- ERLJ, Renato; 12 Crocker Circle, West Newton, Massa chusetts 02465 (US). (74) Agent: REID, Andrea L., C. et al; One International Place, 40th Floor, 100 Oliver Street, Boston, Massachusetts 021 10-2605 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
    [Show full text]
  • Total Synthesis of Sporolide B
    Kanai's Lab Literature Seminar (B4 part) Nov. 10th 2010 Junya Kawai (B4) Total Synthesis of Sporolide B Isolation: from Salinospora tropica (a marine actinomyceta), and it also produces salinosporamide A, a potent inhibitor of the 20S proteasome. Structure: determined in 2005 (Fenical et al., Org. Lett., 2005, 7, 2731-2734) 7 rings, 10 stereogenic centers, and 22 out of 24 carbons are either oxygenated or sp2 hybridized. Including highly substituted indane system, a 1,4-dioxane ring, an epoxy cyclohexenone hemiacetal, and 13-membered macrolide moiety. Difference between sporolide A and B is only the location of chlorine atom on the benzenoid structure. Biological activity: None (but the precursor enediyne compound is considered to have an antitumor activity) Synthetic study: K. Gademann et al., Synthesis, 2010, 4, 631-642 (Biomimetic method) Total synthesis: K. C. Nicolaou et al., Angew. Chem. Int. Ed. 2009, 48, 3449-3453 (Sporolide B ) K. C. Nicolaou et al., J. Am. Chem. Soc. 2010, 132,11350-11363 (Sporolide B, 9-epi-sporolide B) Synthesis of sporolide A has never been reported. Contents 1. Biomimetic approach 1-1. Hypothetical biosynthesis of sporolides 1-2. Bergman cycloaromatization 1-3. Nucleophilic addition to p-benzyne 1-4. Gademann's synthetic study 2. Nicolaou's approach 2-1. Retrosynthetic analysis 2-2. Hetero [4+2] cycloaddition 2-3. Regioselective [2+2+2] cycloaddition 2-4. Model studies about cycloaddition 2-5. Total synthesis of sporolide B salinosporamide A Angew. Chem. Int. Ed., 2010, 49, 2 Chem. Soc. Rev., 2009, 38, 2993 1 1. Biomimetic approach Moore et al., PNAS, 2007, 104, 10376-10381 Moore et al., J.
    [Show full text]
  • Studies on the Biosynthesis and Isolation of the Biosynthetic Gene Cluster for the Salinosporamides of the Marine Bacterium Salinospora Tropica
    Studies on the Biosynthesis and Isolation of the Biosynthetic Gene Cluster for the Salinosporamides of the Marine Bacterium Salinospora tropica Item Type text; Electronic Dissertation Authors Beer, Laura Lynn Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 24/09/2021 21:49:03 Link to Item http://hdl.handle.net/10150/194242 STUDIES ON THE BIOSYNTHESIS AND ISOLATION OF THE BIOSYNTHETIC GENE CLUSTER FOR THE SALINOSPORAMIDES OF THE MARINE BACTERIUM SALINISPORA TROPICA by Laura Lynn Beer ___________________________ Copyright © Laura Lynn Beer 2006 A Dissertation Submitted to the Faculty of the DEPARTMENT OF PHARMACOLOGY AND TOXICOLOGY In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY In the Graduate College THE UNIVERSITY OF ARIZONA 2006 2 THE UNIVERSITY OF ARIZONA GRADUATE COLLEGE As members of the Dissertation Committee, we certify that we have read the dissertation prepared by Laura Lynn Beer entitled Studies on the Biosynthesis and Isolation of the Biosynthetic Gene Cluster for the Salinosporamides of the Marine Bacterium Salinispora tropica and recommend that it be accepted as fulfilling the dissertation requirement for the Degree of Doctor of Philosophy ________________________________________________Date: June 27, 2006 Bradley S. Moore ________________________________________________Date: June 27, 2006 Laurence Hurley ________________________________________________Date: June 27, 2006 Elaine Jacobson ________________________________________________Date: June 27, 2006 Matthew Cordes Final approval and acceptance of this dissertation is contingent upon the candidate’s submission of the final copies of the dissertation to the Graduate College.
    [Show full text]
  • Molecular Blueprints for Antitumor Drugs
    J Ind Microbiol Biotechnol (2013) 40:1181–1210 DOI 10.1007/s10295-013-1331-1 REVIEW Microbial natural products: molecular blueprints for antitumor drugs Lesley-Ann Giddings • David J. Newman Downloaded from https://academic.oup.com/jimb/article/40/11/1181/5994885 by guest on 06 October 2021 Received: 2 April 2013 / Accepted: 7 August 2013 / Published online: 3 September 2013 Ó Society for Industrial Microbiology and Biotechnology (Outside the USA) 2013 Abstract Microbes from two of the three domains of life, Introduction the Prokarya, and Eukarya, continue to serve as rich sources of structurally complex chemical scaffolds that Although Man has used natural product extracts to treat have proven to be essential for the development of anti- diseases for thousands of years, the era of modern che- cancer therapeutics. This review describes only a handful motherapy began in the 1940s with the use of nitrogen of exemplary natural products and their derivatives as well mustards, hormones, and folic acid antagonists. During as those that have served as elegant blueprints for the World War II (1939–1945), the demand for penicillin, in development of novel synthetic structures that are either addition to other new antibiotics, led to major pharma- currently in use or in clinical or preclinical trials together ceutical companies forming large research programs cen- with some of their earlier analogs in some cases whose tered on natural products discovery. These programs aimed to failure to proceed aided in the derivation of later com- identify new secondary metabolites with a variety of novel pounds. In every case, a microbe has been either identified biological activities, including anticancer activities.
    [Show full text]
  • DCTD 2010 Program Accomplishments
    Division of Cancer Treatment and Diagnosis National Cancer Institute 2010 Program Accomplishments 2010 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health NATIONAL CANCER INSTITUTE DIVISION OF Cancer Treatment and Diagnosis Program Accomplishments 2010 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health TABLE OF CONTENTS PREFACE 4 DIVISION OF CANCER TREATMENT AND DIAGNOSIS 6 Overview 7 Major Initiatives and Accomplishments 10 CANCER DIAGNOSIS PROGRAM 26 Overview 27 Structure and Function 30 Program Accomplishments 33 Future Initiatives 47 Selected Publications 48 CANCER IMAGING PROGRAM 54 Overview 55 Structure and Function 58 Program Accomplishments 61 Selected Publications 80 CANCER THERAPY EVALUATION PROGRAM 86 Overview 87 Program Accomplishments 93 Future Directions 118 Selected Publications 119 DEVELOPMENTAL THERAPEUTICS PROGRAM 124 Overview 125 Structure and Function 130 Program Accomplishments 131 Selected Publications 156 2 DCTD PROGRAM ACCOMPLISHMENTS 2010 RADIATION RESEARCH PROGRAM 160 Overview 161 Structure and Function 163 Program Accomplishments 167 Future Initiatives 169 Selected Publications 172 TRANSLATIONAL RESEARCH PROGRAM 178 Overview 179 Background 183 Program Accomplishments 186 Program Collaborations 197 Future Initiatives 201 Selected Publications 201 BIOMETRIC RESEARCH BRANCH 204 Overview 205 Background 205 Program Accomplishments 208 Future Initiatives 218 Selected Publications 219 OFFICE OF CANCER COMPLEMENTARY AND ALTERNATIVE MEDICINE 226 Overview 227 Background 227 Collaborations 232 Future Initiatives 235 Selected Publications 235 APPENDIX 238 Division of Cancer Treatment and Diagnosis Staff Roster 239 DIVISION OF CANCER TREATMENT AND DIAGNOSIS 3 PREFACE This edition of Program Accomplishments of the Division of Cancer Treatment and Diagnosis (DCTD) offers a multi-year review of the undertakings and achievements of this segment of the National Cancer Institute (NCI).
    [Show full text]
  • University of California, San Diego
    UC San Diego UC San Diego Electronic Theses and Dissertations Title New convertible isocyanides for the Ugi Reaction : application to the stereoselective synthesis of omuralide Permalink https://escholarship.org/uc/item/9g1346tj Author Gilley, Cynthia Brooke Publication Date 2008 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA, SAN DIEGO New Convertible Isocyanides for the Ugi Reaction; Application to the Stereoselective Synthesis of Omuralide A Dissertation submitted in partial satisfaction of the Requirements for the degree Doctor of Philosophy in Chemistry by Cynthia Brooke Gilley Committee in charge: Professor Yoshihisa Kobayashi, chair Professor Yitzhak Tor Professor Jerry Yang Professor Wei Wang Professor William Fenical 2008 © Cynthia Brooke Gilley, 2008 All rights reserved. The Dissertation of Cynthia Brooke Gilley is approved, and it is acceptable in quality and form for publication on microfilm: chair University of California, San Diego 2008 iii To my mother, Laurie I feel as though I am the luckiest daughter alive and To the rest of my family Thank you for your encouragement and love iv TABLE OF CONTENTS Signature Page…………………………………………………………………... iii Dedication………………………………………………………………………. iv Table of Contents……………………………………………………………….. v List of Abbreviations……………………………………………………………. xi List of Figures………………………………………………………………….... xv List of Schemes…………………………………………………………………. xvi List of Tables…………………………………………………………………… xxi Acknowledgments………………………………………………………………. xxii Vita……………………………………………………………………………… xxiv Abstract………………………………………………………………………….. xxv CHAPTER ONE 1.1 Fused γ-Lactam-β-lactone Natural Products: Structure, Isolation, & Bioactivity……………………………………… 1 1.1.1 Lactacystin……………………………………………………... 1 1.1.1.1 Omuralide: Biologically Active Form………………. 2 1.1.2 The Salinosporamides………………………………………….. 3 1.1.3 The Cinnabaramides……………………………………………. 4 1.2 Proteasome Inhibition…………………………………………………… 5 1.2.1 The Proteasome: Structure and Function……………………….
    [Show full text]
  • Salinosporamide a (NPI-0052) Potentiates Apoptosis, Suppresses Osteoclastogenesis, and Inhibits Invasion Through Down-Modulation of NF-␬B–Regulated Gene Products
    CHEMOKINES, CYTOKINES, AND INTERLEUKINS Salinosporamide A (NPI-0052) potentiates apoptosis, suppresses osteoclastogenesis, and inhibits invasion through down-modulation of NF-␬B–regulated gene products Kwang Seok Ahn,1 Gautam Sethi,1 Ta-Hsiang Chao,2 Saskia T. C. Neuteboom,2 Madan M. Chaturvedi,1,3 Michael A. Palladino,2 Anas Younes,4 and Bharat B. Aggarwal1 1Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston; 2Nereus Pharmaceuticals, San Diego, CA; 3Department of Zoology, University of Delhi, Delhi, India, and 4Department of Lymphoma/Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston Salinosporamide A (also called NPI-0052), survivin), invasion (matrix metallopro- salinosporamide A inhibited TNF-induced recently identified from the marine bacte- teinase-9 [MMP-9] and ICAM-1), and inhibitory subunit of NF-␬B ␣ (I␬B␣) deg- rium Salinispora tropica, is a potent inhib- angiogenesis (vascular endothelial radation, nuclear translocation of p65, itor of 20S proteasome and exhibits thera- growth factor [VEGF]). Salinosporamide and NF-␬B-dependent reporter gene ex- peutic potential against a wide variety of A also suppressed TNF-induced tumor pression but had no effect on I␬B␣ kinase tumors through a poorly understood cell invasion and receptor activator of activation, I␬B␣ phosphorylation, or I␬B␣ mechanism. Here we demonstrate that nuclear factor ␬B ligand (RANKL)-in- ubiquitination. Thus, overall, our results salinosporamide A potentiated the apo- duced osteoclastogenesis. We also found indicate that salinosporamide A enhances ptosis induced by tumor necrosis factor that it suppressed both constitutive and apoptosis, suppresses osteoclastogen- ␣ (TNF), bortezomib, and thalidomide, inducible NF-␬B activation.
    [Show full text]
  • UNIVERSITY of CALIFORNIA, SAN DIEGO Investigations Into the Biosynthesis of Salinosporamide A
    UNIVERSITY OF CALIFORNIA, SAN DIEGO Investigations into the biosynthesis of salinosporamide A: new insights on PKS extender units and the origin of a nonproteinogenic amino acid A Dissertation submitted in partial satisfaction of the Requirements for the degree Doctor of Philosophy in Oceanography by Yuan Liu Committee in charge: Professor Bradley S. Moore, Chair Professor William Fenical Professor William Gerwick Professor Yoshihisa Kobayashi Professor Emmanuel Theodorakis 2010 © Yuan Liu, 2010 All rights reserved. The Dissertation of Yuan Liu is approved, and it is acceptable in quality and form for publication on microfilm: Chair University of California, San Diego 2010 iii To my wife Crystal and our daughter Hannah and To my parents, Fu-ru Liu and Xue-ying Gao Thank you for your encouragement and love iv TABLE OF CONTENTS Signature Page…………………………………………………………………... iii Dedication……………………………………………………………………….. iv Table of Contents………………………………………………………………… v List of Abbreviations…………………………………………………………….. ix List of Figures…………………………………………………………………..... xiii List of Tables…………………………………………………………………….. xvii Acknowledgments……………………………………………………………….. xviii Vita………………………………………………………………………………. xx Abstract…………………………………………………………………………... xxi CHAPTER ONE: INTRODUCTION……………………………………………. 1 1.1 Natural products as a source of therapeutic agents……………………... 1 1.1.1 The history of natural products as drugs……………………….. 1 1.1.2 Natural products as clinical agents …….……………………… 3 1.1.3 Genome mining for natural products discovery……………….. 6 1.2 Polyketide and nonribosomal peptide natural products ………………... 9 1.3 Proteasome and its inhibitors………………………………………….... 13 1.3.1 Structure and function of the proteasome……………………… 13 1.3.2 Proteasome inhibitors……………………….…………………. 16 1.3.2.1 Synthetic inhibitors: peptide aldehyde, vinyl sulfones, and boronates………………………… 17 1.3.2.2 Natural product inhibitors…………………................ 20 1.3.2.2.1 α’, β’-epoxyketones and TMC-95s……….....
    [Show full text]
  • Computational Methodologies in the Exploration of Marine Natural Product Leads
    marine drugs Review Computational Methodologies in the Exploration of Marine Natural Product Leads Florbela Pereira * and Joao Aires-de-Sousa * LAQV and REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal * Correspondence: fl[email protected] (F.P.); [email protected] (J.A.-d.-S.); Tel.: +351-21-2948300 (F.P.); +351-21-2948300 (J.A.-d.-S.) Received: 14 June 2018; Accepted: 6 July 2018; Published: 13 July 2018 Abstract: Computational methodologies are assisting the exploration of marine natural products (MNPs) to make the discovery of new leads more efficient, to repurpose known MNPs, to target new metabolites on the basis of genome analysis, to reveal mechanisms of action, and to optimize leads. In silico efforts in drug discovery of NPs have mainly focused on two tasks: dereplication and prediction of bioactivities. The exploration of new chemical spaces and the application of predicted spectral data must be included in new approaches to select species, extracts, and growth conditions with maximum probabilities of medicinal chemistry novelty. In this review, the most relevant current computational dereplication methodologies are highlighted. Structure-based (SB) and ligand-based (LB) chemoinformatics approaches have become essential tools for the virtual screening of NPs either in small datasets of isolated compounds or in large-scale databases. The most common LB techniques include Quantitative Structure–Activity Relationships (QSAR), estimation of drug likeness, prediction of adsorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, similarity searching, and pharmacophore identification. Analogously, molecular dynamics, docking and binding cavity analysis have been used in SB approaches.
    [Show full text]