Farnesyltransferase Inhibitors in Cancer Therapy PDF
Preview Farnesyltransferase Inhibitors in Cancer Therapy
FARNESYLTRANSFERASE INHIBITORS IN CANCER THERAPY CANCER DRUG DISCOVERY AND DEVELOPMENT Beverly A. Teicher, Series Editor 10. Matrix Metalloproteinase Inhibitors in Cancer Therapy, edited by Neil J Clendeninn and KrzysztoJA ppelt, 2000 9. Tumor Suppresor Genes in Human Cancer, edited by David E. Fisher, 2000 8. Farnesyltransferase Inhibitors in Cancer Therapy, edited by Said M Sebti and Andrew D. Hamilton, 2000 7. Platinum-Based Drugs in Cancer Therapy, edited by Lloyd R. Kelland and Nicholas P Farrell, 2000 6. Signaling Networks and Cell Cycle Control: The Molecular Basis of Cancer and Other Diseases, edited by J Silvio Gutkind, 2000 5. Apoptosis and Cancer Chemotherapy, edited by John A. Hickman and Caroline Dive, 1999 4. Antifolate Drugs in Cancer Therapy, edited by Ann L. Jackman, 1999 3. Antiangiogenic Agents in Cancer Therapy, edited by Beverly A. Teicher, 1999 2. Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval, edited by Beverly A. Teicher, 1997 1. Cancer Therapeutics: Experimental and Clinical Agents, edited by Beverly A. Teicher, 1997 F ARNESYLTRANSFERASE INHIBITORS IN CANCER THERAPY Edited by M. SAID SEBTI H Lee Mojfitt Cancer Center and Research Institute, Tampa, FL and D. ANDREW HAMILTON Yale University, New Haven, CT * Springer Science+Business Media, LLC © 200 I Springer Science+ Business Media New York Urspliing1ich erschienen bei H umana Press 200 I Softcover reprint of the hardcover 1st edition 2001 All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise without written permission from the Publisher. All articles, comments, opinions, conclusions, or recommendations are those of the author(s), and do not necessarily reflect the views of the publisher. The crystal structure of protein farnesyltransferase has provided a structural framework for understanding how inhibitors and substrates interact with this therapeutically important enzyme. Shown here, the beta subunit of this heterodimeric enzyme is lined with aromatic residues that interact with both substrates in the reaction. For more detail please see Chapter 3. Cover artwork courtesy of Drs. Lorena Beese and Stephen Long. Cover design by Patricia F. Cleary. This publication is printed on acid-free paper.® ANSI 239.48-1984 (American National Standards Institute) Permanence of Paper for Printed Library Materials. Photocopy Authorization Policy: Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Springer Science+ Business Media, LLC, provided that the base fee of US $10.00 per copy, plus US $00.25 per page, is paid directly to the Copyright Clearance Center at 222 Rosewood Drive, Danvers, MA 01923. For those organizations that have been granted a photocopy license from the CCC, a separate system ofp ayment has been arranged and is acceptable to Springer Science+B usiness Media, LLC . The fee code for users of the Transactional Reporting Service is: [0-89603-629-4/0 I $10.00 + $00.25]. Library of Congress Cataloging-in-Publication Data Farnesyltransferase inhibitors in cancer therapy/edited by Said M. Sebti and Andrew D. Hamilton. p.;cm.--(Cancer drug discovery and development) Includes bibliographical references and index. ISBN 978-1-4684-9606-2 ISBN 978-1-59259-013-1 (e Book) DOI 10.1007/978-1-59259-013-1 I. Dimethylalyltranstransferase--lnhibitors--Therapeutic use--Testing. 2. Cancer--Chemotherapy. I. Sebti, Said M. II. Hamilton, Andrew D. Ill. Series. [DNLM: I. Dimethylalyltranstransferase--antagonists & inhibitors. 2. Antineoplastic Agents--chemical synthe- sis. 3. Drug design. 4. Enzyme Inhibitors--therapeutic use. 5. Genes, ras. QU 141 P927 2000] RC271.D534 P74 2000 616.99'4061--dc21 00-035038 PREFACE Most presently used anticancer drugs were developed based on their anti proliferative rather than anti oncogenic properties and consequently suffer from two major limitations. Many are cytotoxic and cause major thwarted effects owing to their ability to inhibit indiscriminately the growth of fast dividing cells. Drug resistance, the second major limitation oft hese drugs, arises primarily from the lack ofa ctivity against the more slowly growing solid tumors. The recent explosion of knowledge gained from genes capable of causing cancer, and the pivotal role they play in growth factor signal transduction, have opened up new avenues for rationally designing novel anticancer drugs. One of the best studied signal transduction pathways, which contains a gold mine of anticancer drug discovery targets, is that of receptor tyrosine kinase signaling. A key molecular switch within this pathway is a small GTPase called Ras. Ras mediated the transfer of biological information from extracellular signals to the nucleus and is a major regulator of cell division. Oncogenic mutations in the ras gene are found in about 30% of all human cancers and result in a constitutively activated protein that sends uninterrupted signals to the nucleus. Over the last two decades several approaches have failed to reverse the constitutive activation of the Ras protein. Recently, however, the realization that famesylation, a lipid posttrans lational modification, of Ras is required for its cancer-causing activity, prompted an intense search for famesyltransferase inhibitors as novel anticancer agents. Farnesyltransferase Inhibitors in Cancer Therapy describes the efforts of several groups to design, synthesize, and evaluate the biological activities offamesyltransferase inhibitors. Rational design of small organic molecules that mimic the carboxyl terminal tetrapeptide famesylation site of Ras resulted in pharmacological agents capable of inhibiting Ras processing and selectively antagonizing oncogenic signaling and sup pressing human tumor growth in mouse models without side effects. These agents are presently undergoing advanced preclinical studies. Several important issues, such as the mechanism of action of famesyltransferase inhibitors and the potential mechanisms of resistance to inhibition of K-Ras famesylation, are also discussed. Furthermore, the recent observation that K-Ras 4B, the most frequently mutated form of Ras in human tumors, can be geranylgeranylated and that, in addition to Ras, there are other geranylgeranylated small G-proteins that play an important role in smooth muscle pro liferation and apoptosis, stimulated the search for inhibitors of a closely related enzyme, geranylgeranyltransferase I. Thus, the current volume also discusses geranyl geranyltransferase I inhibitors as modulators of cell cycle and apoptosis, and as potential therapeutic agents for cardiovascular disease. Saia M. Sebti Andrew D. Hamilton v CONTENTS Preface .................................................................................................................................. v Contributors ......................................................................................................................... ix 1 Signal Transduction Pathways: A Goldmine for Therapeutic Targets .............................................................................................. . Paul Workman 2 The Biochemistry of Famesyltransferase and Geranylgeranyltransferase I ..................................................... 21 Chih-Chin Huang, Carol A. Fierke, and Patrick J. Casey 3 Structures of Protein Famesyltransferase ........................................... 37 Stephen B. Long and Lorena S. Beese 4 Peptidomimetic-Based Inhibitors of Famesyltransferase .................. 49 David Knowles, Jiazhi Sun, Saul Rosenberg, Sai'd M. Sebti, and Andrew D. Hamilton 5 Antitumor Efficacy of a Famesyltransferase Inhibitor in Transgenic Mice ......................................................................... 65 Jackson B. Gibbs, Samuel L. Graham, George D. Hartman, Kenneth S. Koblan, Nancy E. Kohl, Charles Omer, Angel Pellicier, Jolene Windle, and Allen Oliff 6 Development of Famesyltransferase Inhibitors as Potential Antitumor Agents ............................................................................ 71 Veeraswamy Manne, Frank Lee, Ning Yan, Craig Fairchild, and William C. Rose 7 Tricyclic Famesyl Protein Transferase Inhibitors: Antitumor Activity and Effects on Protein Prenylation ................. 87 W. Robert Bishop, James J.-K. Pai, Lydia Armstrong, Marguerite B. Dalton, Ronald J. Doll, Arthur Taveras, George Njoroge, Michael Sinensky, Fang Zhang, Ming Liu, and Paul Kirschmeier 8 Histidylbenzylglycinamides: A Novel Class ofFarnesyl Diphosphate- Competitive Peptidic Farnesyltransferase Inhibitors ........................ 103 Judith S. Sebolt-Leopold, Daniele M. Leonard, and W. R. Leopold 9 From Random Screening of Chemical Libraries to the Optimization of FPP-Competitive Inhibitors of Famesyltransferase .................... 115 Patrick Mailliet, Abdel Laoui, Jean-Dominique Bourzat, Marc Capet, Michel Cheve, Alain Commerfon, Norbert Dereu, Alain LeBrun, Jean-Paul Martin, Jean-Franfois Peyronel, Christophe Salagnad, Fabienne Thompson, Martine Zucco, Jean-Dominique Guitton, Guy Pantel, Marie-Christine Bissery, Clive Brealey, Jacques Lavayre, Yves Lelievre, Jean-Franfois Riou, Patricia Vrignaud, Marc Duchesne, and Franfois Lavelle Vll viii Contents 10 Genetic Analysis ofFTase and GGTase I and Natural Product Farnesyltransferase Inhibitors ...................................................... 145 Fuyuhiko Tamanoi, Keith Del Villar, Nicole Robinson, MeeRhan Kim, Jun Urano, and Wenli Yang 11 Effects of Farnesyltransferase Inhibitors on Cytoskeleton, Cell Transformation, and Tumorigenesis: The FTI-Rho Hypothesis ............................................................... 159 George C. Prendergast 12 Prenyltransferase Inhibitors as Radiosensitizers .............................. 171 Eric J. Bernhard, Ruth J. Muschel, Elizabeth Cohen-Jonathan, Gilles Favre, Andrew D. Hamilton, Sai"d M. Sebti, and W. Gillies McKenna 13 Farnesyltransferase and Geranylgeranyltransferase I Inhibitors as Novel Agents for Cancer and Cardiovascular Diseases .......... 197 Sai"d M. Sebti and Andrew D. Hamilton 14 Protein Prenylation in Trypanosomatids: A New Piggy-Back Medicinal Chemistry Target for the Development ofA gents Against Tropical Diseases ............................................................ 221 Michael H. Gelb, Frederick S. Buckner, Kohei Yokoyama, Junko Ohkanda, Andrew D. Hamilton, Lisa Nguyen, Bartira Rossi-Bergmann, Kenneth D. Stuart, Saia M. Sebti, and Wesley C. Van Voorhis 15 Early Clinical Experience with Farnesyl Protein Transferase Inhibitors: From the Bench to the Bedside ................................... 233 Amita Patnaik and Eric K. Rowinsky 16 Phase I Trial of Oral R115777 in Patients with Refractory Solid Tumors: Preliminary Results .............................................. 251 Gary R. Hudes and Jessie Schol 17 Farnesyltransferase and Geranylgeranyltransferase Inhibitors: The Saga Continues ...................................................................... 255 Adrienne D. Cox, L. Gerard Toussaint III, James J. Fiordalisi, Kelley Rogers-Graham, and Channing J. Der Index ....................................................................................................................... 275 CONTRIBUTORS LYDIA ARMSTRONG, PHD· Schering-Plough Research Institute, Kenilworth, NJ LORENA S. BEESE, PHD • Department of Biochemistry, Duke University Medical Center, Durham NC ERIC 1. BERNHARD, PHD • Department ofR adiation Oncology, University ofP ennsylvania Medical Center, Philadelphia, PA W. ROBERT BISHOP, PHD· Schering-Plough Research Institute, Kenilworth, NJ MARIE-CHRISTINE BISSERY, PHD • Rhone-Poulenc-Rorer S.A., Vitry sur Seine, France lEAN-DoMINIQUE BOURZAT, PHD· Rhone-Poulenc-Rorer S.A., Vitry sur Seine, France CLIVE BREALEY, PHD· Rhone-Poulenc-Rorer S.A., Vitry sur Seine, France FREDERICK S. BUCKNER, PHD· Department of Medicine, University of Washington, Seattle, WA MARC CAPET, PHD • Rhone-Poulenc-Rorer S.A., Vitry sur Seine, France PATRICK 1. CASEY, PHD • Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC MICHEL CHEVE, PHD • Rhone-Poulenc-Rorer S.A., Vitry sur Seine, France ELIZABETH COHEN-JONATHAN, MD, PHD • Department of Radiation Oncology, University ofP ennsylvania Medical Center, Philadelphia, PA ALAIN COMMERC;:ON, PHD· Rhone-Poulenc-Rorer S.A., Vitry sur Seine, France ADRIENNE D. Cox, PHD· Departments of Radiation Oncology, Pharmacology, and Curriculum in Genetics and Molecular Biology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC MARGUERITE B. DALTON, PHD· Department ofB iochemistry and Molecular Biology, East Tennessee State University, Johnson City, TN KEITH DEL VILLAR, PHD • Department ofM icrobiology and Molecular Genetics, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA CHANNING J. DER, PHD • Department ofP harmacology and Curriculum in Genetics and Molecular Biology, Curriculum in Toxicology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC NORBERT DEREU, PHD • Rhone-Poulenc-Rorer S.A., Vitry sur Seine, France RONALD J. DOLL, PHD· Schering-Plough Research Institute, Kenilworth, NJ MARC DUCHESNE, PHD • Rhone-Poulenc-Rorer S.A., Vitry sur Seine, France CRAIG FAIRCHILD, PHD· Oncology Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ GILLES FAVRE, PHD • Centre Claudius Regaud, Toulouse, France CAROL A. FIERKE, PHD· Department ofB iochemistry, Duke University Medical Center, Durham, NC JAMES J. FIORDALlSI, PHD • Department ofR adiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC MICHAEL H. GELB, PHD • Departments of Chemistry and Biochemistry, University of Washington, Seattle, WA JACKSON B. GIBBS, PHD· Department ofC ancer Research, Merck Research Laboratories, West Point, PA SAMUEL L. GRAHAM, PHD • Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA ix x Contributors JEAN-DoMINIQUE GUITTON, PHD • Rhone-Poulenc-Rorer S.A., Vitry sur Seine, France ANDREW D. HAMILTON, PHD • Department ofC hemistry, Yale University, New Haven, CT GEORGE D. HARTMAN, PHI) • Department ofM edicinal Chemistry, Merck Research Laboratories, West Point, PA CHIH-CHIN HUANG, PHD • Department ofB iochemistry, Duke University Medical Center. DurhamNC GARY R. HUDES, MD • Department ofM edical Oncology, Fox Chase Cancer Center, Philadelphia, PA MEERHAN KIM, PHD • Department ofM icrobiology and Molecular Genetics, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA PAUL KIRSCHMEIER, PHD • Schering-Plough Research Institute, Kenilworth, NJ KENNETH S. KOSLAN, PHD· Department ofC ancer Research, Merck Research Laboratories, West Point, PA NANCY E. KOHL, PHD· Department of Cancer Research, Merck Research Laboratories, West Point, PA DAVID KNOWLES, PHD • Department of Chemistry, University of Pittsburgh, PA ASDEL LAOUI, PHD • Rhone-Poulenc-Rorer S.A., Vitry sur Seine, France JACQUES LAVAYRE, PHD· Rhone-Poulenc-Rorer S.A., Vitry sur Seine, France FRAN<;:OIS LAVELLE, PHD· Rhone-Poulenc-Rorer S.A., Vitry sur Seine, France ALAIN LEBRUN, PHD • Rhone-Poulenc-Rorer S.A., Vitry sur Seine, France FRANK LEE, PHD • Oncology Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ YVES LELIEVRE, PHD • Rhone-Poulenc-Rorer S.A., Vitry sur Seine, France DANIELE M. LEONARD, PHD • Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Co., Ann Arbor, MI W. R. LEOPOLD, PHD· Department of Cancer Research, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Co., Ann Arbor, MI MING LIU, PHD • Schering-Plough Research Institute, Kenilworth, NJ STEPHEN B. LONG, PHD • Department ofB iochemistry, Duke University Medical Center, Durham, NC PATRICK MAILLIET, MD· Rhone-Poulenc-Rorer S.A., Vitry sur Seine, France VEERASWAMY MANNE, PHD· Oncology Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ JEAN-PAUL MARTIN, MD • Rhone-Poulenc-Rorer S.A., Vitry sur Seine, France W. GILLIES McKENNA, MD, PHD • Department ofR adiation Oncology, University ofP ennsylvania Medical Center, Philadelphia, PA RUTH J. MUSCHEL, MD, PHD • Department ofP athology and Laboratory Medicine, University ofP ennsylvania Medical Center, Philadelphia, PA LISA NGUYEN, PHD • Department ofM edicine, University of Washington, Seattle, WA GEORGE NJOROGE, PHD • Schering-Plough Research Institute, Kenilworth, NJ JUNKO OHKANDA, PHD· Department of Chemistry, Yale University, New Haven, CT ALLEN OLIFF, MD· Department of Cancer Research, Merck Research Laboratories, West Point, PA CHARLES OMER, PHD • Department of Cancer Research, Merck Research Laboratories, West Point, PA JAMES J.-K. PAl, PHD· Schering-Plough Research Institute, Kenilworth, NJ GUY PANTEL, MD· Rhone-Poulenc-Rorer S.A., Vitry sur Seine, France
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