Send Orders for Reprints to reprints@benthamscience.net Current Proteomics, 2014, 11, 000-000 1 1570-1646/14 $58.00+.00 ©2014 Bentham Science Publishers Heat Shock Protein 90 Inhibitors in Oncology Aykut Özgür 1 and Yusuf Tutar 2 * 1 Gaziosmanpaa University, Faculty of Natural Sciences and Engineering, Department of Bioengineering, Tokat, Turkey; 2 Cumhuriyet University, Faculty of Pharmacy, Department of Basic Sciences, Division of Biochemistry, Sivas, Turkey Abstract: Heat shock protein 90 (Hsp90) is highly conserved chaperone protein which plays vital roles in stabilization, regulation and folding of client proteins in cancer cells. Client proteins are key macromolecules for carcinogenesis and their maintenance (stabilization and protection from aggregation and misfolding) is provided by Hsp90 chaperone activity. Hsp90 allows proliferation of cancer cells by keeping misfolded client proteins in their proper functional folded form and suppresses apoptotic pathways for cancer cell survival. For this purpose, Hsp90 inhibitors have become an important growing class of antitumor agents in pharmaceutical industry. To date, numerous compounds have been tested as antican- cer drugs in preclinical and clinical studies. Hsp90 inhibitors may be categorized into two main classes: natural and syn- thetic inhibitors. In this review, we will discuss the general properties and structure of both natural inhibitors (geldanamy- cin, 17-AAG, 17-DMAG, herbimycin, radicicol, novobiocin, (-)-EGCG, derrubone, gedunin, celastrol and their deriva- tives) and synthetic inhibitors (purine scaffold inhibitors, pyrazole scaffold inhibitors, SNX-2112, STA9090 and their de- rivatives) along with their therapeutic strategies in many different cancer types. Keywords: Chaperone, Hsp90, Hsp90 inhibitors, cancer, geldanamycin, client proteins. 1. INTRODUCTION Heat shock proteins (Hsps) are highly conserved protein family involved in protein disaggregation, proper folding of newly synthesized and nascent proteins, degradation of mis- folded proteins, cell cycle control and signal transduction. Hsps are classified according to their molecular weights: small Hsps (<40 kDa), Hsp40, Hsp60, Hsp70, Hsp90, and Hsp100 which are localized in different cellular compart- ments such as cytosol, mitochondria, and endoplasmic re- ticulum. Hsps are highly expressed in response to external and cellular stresses including infections, drugs, heat, oxida- tive stress, fever, inflammation, hormonal stimulation, and malignancy. Consequently, Hsps play significant roles in cellular homeostasis and cytoprotective processes during normal cell growth and for survival during and after various cellular stresses. Therefore, expression level of Hsps is asso- ciated with numerous diseases (i.e. cancer, neurodegenera- tive diseases and infection diseases) [1-8]. Cancer cells metabolic rates are faster compared to nor- mal healthy cells, and they are exposed to intensive cellular stress. Therefore, cancer cells need more Hsp macromole- cules and Hsps are overexpressed in a wide range of human cancers. Hsps overexpression in tumor means either poor prognosis or higher resistance to anticancer treatment. Par- ticularly, Hsp90 is a validated novel therapeutic target for cancer. In cancer cells, Hsp90 participates in maintaining the conformation, stability, and cellular localization of onco- genic proteins and these proteins play key roles in tumori- genesis. As Hsp90 is inhibited, oncogenic proteins cannot be *Address correspondence to this author at the Cumhuriyet University, Fac- ulty of Pharmacy, Department of Basic Sciences, Division of Biochemistry, Sivas, Turkey; Tel: +90 346-219-1010 ext. 3907; E-mails: ytutar@cumhuriyet.edu.tr or ytutar@yahoo.com folded properly, thus they cannot perform their roles in tu- morigenesis. Thus, Hsp90 inhibition was accepted as essen- tial strategy for cancer therapy [9-12]. 1.1. Structure and Functions of HSP90 In unstressed eukaryotic cells, Hsp90 is one of the most abundant molecular chaperones that correspond to 1-2% of all cellular proteins [1, 11, 12]. Hsp90 is a large conserved homodimeric protein which contains nine helices, eight anti- parallel beta pleated sheets and several alpha/beta sand- wiches. In higher eukaryotes, Hsp90 family comprises both inducible and constitutively expressed cytosolic isoforms namely Hsp90 and Hsp90. Furthermore, Hsp90 has GRP94 and TRAP1 isoforms in the endoplasmic reticulum and mitochondria respectively. Hsp90 consists of three con- served functional domains: 25 kDa N-terminal domain (NTD), 55 kDa middle domain (MD) and 10 kDa C-terminal domain (CTD). NTD has an ATP binding site that binds to ATP and ADP (Fig. 1). Therefore, NTD performs ATPase activity, and large conformational changes are occurred upon ATP binding and ATP hydrolysis. The CTD has a conserved MEEVD motif which is responsible for the binding of some co-chaperones such as Hsp organizing protein (Hop), FK506-binding protein (FKBP52) and protein phosphatase 5 (PP5). Also, the MD possesses binding sites for co- chaperones and client proteins [1, 13-15]. Proteins need proper three dimensional structures for per- forming cellular functions. Hsp90 and co-chaperones assist protein folding mechanisms, intracellular trafficking of pro- teins and degradation of misfolded proteins.Hsp90 is able to stabilize and degrade misfolded non-native proteins and works coordinately with co-chaperones (Hsp40, Hsp70, Cdc37, p23), partner proteins (Hsp organizing protein (Hop), PP5 and immunophilins (FKBP51, FKBP52, Cyp40) in pro-