Farnesyltransferase inhibitors in cancer therapy PDF
Preview Farnesyltransferase inhibitors in cancer therapy
F I ARNESYLTRANSFERASE NHIBITORS C T IN ANCER HERAPY C D D ANCER RUG ISCOVERY D AND EVELOPMENT Beverly A. Teicher, Series Editor 10. Matrix Metalloproteinase Inhibitors in Cancer Therapy, edited by Neil J. Clendeninn and Krzysztof Appelt, 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 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, Clini- cal Trials, and Approval, edited by Beverly A. Teicher, 1997 1. Cancer Therapeutics: Experimental and Clinical Agents, edited by Beverly A. Teicher, 1997 F ARNESYLTRANSFERASE I NHIBITORS C T IN ANCER HERAPY Edited by S M. S AÏD EBTI H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL and A H NDREW AMILTON Yale University, New Haven, CT H P UMANA RESS T , N J OTOWA EW ERSEY © 2001 Humana Press Inc. 999 Riverview Drive, Suite 208 Totowa, New Jersey 07512 For additional copies, pricing for bulk purchases, and/or information about other Humana titles, contact Humana at the above address or at any of the following numbers: Tel.: 973-256-1699; Fax: 973-256-8341; E-mail:[email protected] or visit our Website: http://humanapress.com 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. Cover illustration: The crystal structure of mammalian protein farnesyltransferase (FTase; red: a subunit; blue: (cid:96)subunit) shown here with bound substrates (yellow: K-Ras peptide; gray: farnesyl diphosphate) and zinc cofactor (pink) has provided a structural framework for understanding how inhibitors and substrates interact with this therapeutically impor- tant enzyme. FTase catalyzes the covalent addition of the farnesyl isoprenoid to small G-proteins, such as Ras, and this posttranslational modification is essential for their activation. Cover artwork courtesy of Dr. Lorena Beese. Cover design by Patricia F. Cleary. This publication is printed on acid-free paper. (cid:39) ANSI Z39.48-1984 (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 Humana Press Inc., 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 of payment has been arranged and is acceptable to Humana Press Inc. The fee code for users of the Transactional Reporting Service is: [0-89603-629-4/01 $10.00 + $00.25]. Printed in the United States of America. 10 9 8 7 6 5 4 3 2 1 Library of Congress Cataloging-in-Publication Data Prenyltransferase inhibitors in cancer therapy/edited by Saïd M. Sebti and Andrew Hamilton. p.;cm.—(Cancer drug discovery and development) Includes bibliographical references and index. ISBN 0-89603-629-4 (alk. paper) 1. Dimethylallyltranstransferase—Inhibitors—Therapeutic use—Testing. 2. Cancer—Chemotherapy.I. Sebti, Saïd M. II.Hamilton, Andrew D. III. Series. [DNLM: 1.Dimethylallyltranstransferase—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 antiproliferative rather than antioncogenic 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 of these drugs, arises primarily from the lack of activity 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 farnesylation, a lipid posttrans- lational modification, of Ras is required for its cancer-causing activity, prompted an intense search for farnesyltransferase inhibitors as novel anticancer agents. Farnesyltransferase Inhibitors in Cancer Therapy describes the efforts of several groups to design, synthesize, and evaluate the biological activities of farnesyltransferase inhibitors. Rational design of small organic molecules that mimic the carboxyl terminal tetrapeptide farnesylation 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 farnesyltransferase inhibitors and the potential mechanisms of resistance to inhibition of K-Ras farnesylation, 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. Saïd M. Sebti Andrew Hamilton v CONTENTS Preface..................................................................................................................................v Contributors.........................................................................................................................ix 1 Signal Transduction Pathways: A Goldmine for Therapeutic Targets............................................................................................... 1 Paul Workman 2 The Biochemistry of Farnesyltransferase and Geranylgeranyltransferase I.....................................................21 Chih-Chin Huang, Carol A. Fierke, and Patrick J. Casey 3 Structures of Protein Farnesyltransferase...........................................37 Stephen B. Long and Lorena S. Beese 4 Peptidomimetic-Based Inhibitors of Farnesyltransferase..................49 David Knowles, Jiazhi Sun, Saul Rosenberg, Saïd M. Sebti, and Andrew D. Hamilton 5 Antitumor Efficacy of a Farnesyltransferase 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 Farnesyltransferase Inhibitors as Potential Antitumor Agents............................................................................71 Veeraswamy Manne, Frank Lee, Ning Yan, Craig Fairchild, and William C. Rose 7 Tricyclic Farnesyl 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 of Farnesyl 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 Farnesyltransferase....................115 Patrick Mailliet, Abdel Laoui, Jean-Dominique Bourzat, Marc Capet, Michel Chevé, Alain Commerçon, Norbert Dereu, Alain LeBrun, Jean-Paul Martin, Jean-François Peyronel, Christophe Salagnad, Fabienne Thompson, Martine Zucco, Jean-Dominique Guitton, Guy Pantel, Marie-Christine Bissery, Clive Brealey, Jacques Lavayre, Yves Lelièvre, Jean-François Riou, Patricia Vrignaud, Marc Duchesne, and François Lavelle vii viii Contents 10 Genetic Analysis of FTase 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, Saïd M. Sebti, and W. Gillies McKenna 13 Farnesyltransferase and Geranylgeranyltransferase I Inhibitors as Novel Agents for Cancer and Cardiovascular Diseases..........197 Saïd M. Sebti and Andrew D. Hamilton 14 Protein Prenylation in Trypanosomatids: A New Piggy-Back Medicinal Chemistry Target for the Development of Agents 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, Saïd 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 LORENAS. BEESE,PHD• Department of Biochemistry, Duke University Medical Center, Durham NC ERICJ. BERNHARD,PHD•Department of Radiation Oncology, University of Pennsylvania 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 JEAN-DOMINIQUE BOURZAT,PHD• Rhone-Poulenc-Rorer S.A., Vitry sur Seine, France CLIVE BREALEY,PHD•Rhone-Poulenc-Rorer S.A., Vitry sur Seine, France FREDERICKS. BUCKNER,PHD• Department of Medicine, University of Washington, Seattle, WA MARC CAPET,PHD•Rhone-Poulenc-Rorer S.A., Vitry sur Seine, France PATRICKJ. CASEY,PHD• Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC MICHEL CHEVÉ,PHD•Rhone-Poulenc-Rorer S.A., Vitry sur Seine, France ELIZABETH COHEN-JONATHAN,MD,PHD• Department of Radiation Oncology, University of Pennsylvania Medical Center, Philadelphia, PA ALAIN COMMERÇON,PHD•Rhone-Poulenc-Rorer S.A., Vitry sur Seine, France ADRIENNED. 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 MARGUERITEB. DALTON,PHD• Schering-Plough Research Institute, Kenilworth, NJ KEITH DEL VILLAR,PHD•Department of Microbiology and Molecular Genetics, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA CHANNINGJ. DER,PHD• Department of Pharmacology 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 RONALDJ. 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 CAROLA. FIERKE,PHD• Department of Biochemistry, Duke University Medical Center, Durham, NC JAMESJ. FIORDALISI,PHD• Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC MICHAELH. GELB,PHD• Departments of Chemistry and Biochemistry, University of Washington, Seattle, WA JACKSONB. GIBBS,PHD• Department of Cancer Research, Merck Research Laboratories, West Point, PA SAMUELL. GRAHAM,PHD• Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA ix
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