Advances in Anticancer Agents in Medicinal Chemistry: Volume 1

Michelle Prudhomme

• Publisher: Bentham Science Publishers
• Print ISBN: 9781608057122
• eBook ISBN: 9781608054930
• Topic: Medicine
• Subtopic: Oncology

Advances in Anticancer Agents in Medicinal Chemistry is an exciting eBook series copmrising a selection of updated articles previously published in the peer-reviewed journal Anti-Cancer Agents in Medicinal Chemistry. The first volume presents reviews of many classes of drugs of contemporary interest for cancer therapy and is devoted to small inhibitors of various proteins involved in cancer development such as casein kinase 2 (CK2), protein kinase B (PKB), mTOR, Hsp90, P-glycoprotein (P-gp), kinesin spindle protein (KSP), cyclooxygenase 2 (COX-2), histone deacetylase enzymes (HDACs) and topoisomerase I.
Advances in Anticancer Agents in Medicinal Chemistry will be of particular interest to readers interested in anticancer drug therapy as the series provides relevant reviews written by experts in this important field.

Recent Advances in Hsp90 Inhibitors as Antitumor Agents

Samir Messaoudi^*, Jean F. Peyrat^*, Jean D. Brion, Mouâd Alami

Univ. Paris-Sud, CNRS, BioCIS-UMR 8076, Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie, IFR 141, 5 rue J.-B. Clément, Châtenay-Malabry, F-92296, France

Abstract

One promising therapeutic strategy for treating cancer is to specifically target signal transduction pathways that have a key role in oncogenic transformation and malignant progression. Hsp90 is an emerging therapeutic target of interest for the treatment of cancer. It is responsible for modulating cellular response to stress by maintaining the function of numerous signaling proteins - known as ‘client proteins’ - that are associated with cancer cell survival and proliferation. Many cancers result from specific mutations in, or aberrant expression of, these client proteins. Small molecule Hsp90 inhibitors bind to the ATP binding pocket, inhibit chaperone function and could potentially result in cytostasis or cell death. Consequently, many client proteins are targeted for degradation via the ubiquitin-proteasome pathway including receptor and non receptor kinases (Erb-B2, epidermal growth factor receptor, and Src family kinases), serine/threonine kinases (c-Raf-1 and Cdk4), steroid hormone receptors (androgen and estrogen), and apoptosis regulators such as mutant p53. Inhibition of Hsp90 function Hsp90 has also proven effective in kiling cancer cells that have developed resistance to targeted therapies such as kinase inhibitors.

This review is intended to update recent developments in new Hsp90 inhibitors as antitumors agents, the design, biological evaluation and their clinical trials studies.

Keywords: : Cancer, heat shock protein 90 (Hsp90), co-chaperone, client proteins, antitumor agents, NTD-Hsp90 inhibitors, CTD-Hsp90 inhibitors, apoptosis, proteasome.

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^* Address correspondence to Samir Messaoudi and Jean F. Peyrat: Univ. Paris-Sud, CNRS, BioCIS-UMR 8076, Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie, IFR 141, 5 rue J.-B. Clément, Châtenay-Malabry, F-92296, France; Tel: [phone]; E.mail: [email protected] and Tel: [phone]; Fax: [phone]; E-mail: [email protected]

Introduction

The 90-kDa chaperone protein (Hsp90) is highly conserved and ubiquitously expressed in all living organisms. It is essential for maintaining the activity of

numerous signaling proteins [1] in the eukaryotic cell. Hsp90 exerts its chaperone function to ensure the correct conformation, activity, intracellular localization and proteolytic turnover of a range of proteins that are involved in cell growth, differentiation and survival [2^-6]. Hsp90 is the most abundant molecular chaperone in these kind of cells, accounting for 1-2% of total protein content. It contains a highly conservated ATP binding domain near its N-terminus, and its chaperoning activity requires both the binding and hydrolysis of ATP at this site [7]. Under non stress conditions, the quaternary structure of Hsp90 is now well established to be a dimeric complex. Each monomer, consists of three well-conserved structural domains: (i) the N-terminal domain (NTD) involved in nucleotides and inhibitors binding (e.g.; radicicol, geldanamycin and derivatives); (ii) the middle domain (MD) involved in the binding of both co-chaperones and client proteins; and (iii) the C-terminal domain (CTD) implicated in dimerization process [8]. This latest CTD which would contain a second nucleotide binding site common to novobiocin, but its crystal structure has yet to be solved. To acquire its full active molecular chaperone activity, Hsp90 operates in concert with molecular chaperones named co-chaperones that combine in various ways to form a series of multimeric protein complexes. The Co-chaperone machinery regulates the ATPase activity of Hsp90 necessary for its biological activity, and includes Hsp70, peptidyl-prolyl isomerases, the immunophilins (FKBP51 and FKBP52) and the cyclophilin CYP40. Others co-chaperones such as p23 [9, 10], recently identified as a prostaglandine E2-Syntase, plays an important role in the activity of a number of transcription factors of the steroid/thyroid receptor family. To ensure their role in the folding of client proteins, these partners interact with Hsp90 through TPR (tetratricopeptide repeats) sequences and affect the balance between stabilization and degradation of client proteins via the ubiquitin-proteasome pathway (Fig. 1).

An interesting recent study investigated Hsp90 conformational changes in solution, shows a long range effects between Hsp90 domains, as the binding of co-chaperones (or inhibitors) at NTD induce conformational changes in the MD and CTD [12].

To date, five isoforms have been identified in the highly conserved Hsp90 family which differs in their cellular localization. The two major cytoplasmic isoforms for this protein identi...

Table of contents

• Welcome
• Table of Contents
• Title
• BENTHAM SCIENCE PUBLISHERS LTD.
• FOREWORD
• PREFACE
• Casein Kinase 2 (CK2) Inhibitors: Emerging Anticancer Therapeutic Agents?
• An Update 2009 – 2012 to “Targeted Small-Molecule Inhibitors of Protein Kinase B as Anticancer Agents”
• Advances in mTOR Inhibitors
• Recent Advances in Hsp90 Inhibitors as Antitumor Agents
• Recent Developments of P-gp Inhibitors
• Progress Review on Kinesin Spindle Protein Inhibitors as Anti-Cancer Agents
• Discovery of Allosteric Inhibitors of Kinesin Spindle Protein (KSP) for the Treatment of Taxane-Refractory Cancer: MK-0731 and Analogs
• Selective Cyclooxygenase-2 Inhibitors for Malignant Glioma Therapy: Molecular Targets Beyond COX-2
• Histone Deacetylase Inhibitors: Their Structure, Function and Potential to Treat Cancer
• Inhibiting Topoisomerase I, an Emerging Treatment for Primary CNS Malignancies