Editorial - (2016) Volume 5, Issue 4

New Generation Cancer Drug Studies: Hsp90 Inhibitors

Lütfi Tutar1, Kübra Açıkalın Coşkun2 and Yusuf Tutar2*
1Department of Biology, Kahramanmaras Sütçü Imam University, Graduate School of Natural and Applied Sciences, Turkey, E-mail: [email protected]
2Department of Basic Sciences, Division of Biochemistry, Faculty of Pharmacy, Cumhuriyet University, Turkey, E-mail: [email protected]
*Corresponding Author: Yusuf Tutar, Professor, Cumhuriyet University, Faculty of Pharmacy, Basic Sciences Department, Division of Biochemistry, 58140, Sivas, Turkey, Tel: 90346 2191010 Exn. 3907, Fax: +903462191634 Email: ,

Abstract

Heat shock protein 90 (Hsp90) is an ATP dependent highly conserved protein that provides client proteins to reach the correct conformation. Hsp90 uses ATPase activity to perform function such as folding for substrate proteins, misfolded protein degradation, cell cycle, and signal transduction.

Keywords: Hsp90 inhibitors; Cancer drugs

Editorial

Heat shock protein 90 (Hsp90) is an ATP dependent highly conserved protein that provides client proteins to reach the correct conformation. Hsp90 uses ATPase activity to perform function such as folding for substrate proteins, misfolded protein degradation, cell cycle, and signal transduction [1,2]. Hsp 90 has 4 isoforms in the cell; inducible form Hsp90α and constitutive form Hsp90β in the cytosol, Grp94 in the endoplasmic reticulum and TRAP1 in the mitochondrial matrix. Hsp90 forms a homodimer and each monomer includes three domains: N-terminal domain (25 kDa) with a high ATP affinity cochaperon binding site, middle domain (35 kDa) process client proteins, and C-terminal domain (12 kDa) has conserved EEVD motif and dimerization region. This homodimer forms a big hydrophobic cavity and this cavity encapsulates client proteins. This hydrophobic environment allows client proteins to fold their native structure. When Hsp90 dimer in open state, N-terminal domains protrude each other and upon client protein entrance the dimer closes around the client protein to provide a suitable hydrophobic place for folding. When ATP binds at high affinity state, dimer closes and ATP hydrolyzes and correctly folded client protein releases from the cavity [1-5] (Figure 1).

single-cell-biology-folding-client-protein

Figure 1: Hsp90 domains and ATPase cycle for folding client protein.

Typical client proteins are tyrosine kinases, metastable signaling proteins, mutated oncogenic proteins, steroid receptors, and cell-cycle regulators. And the client proteins are associated with Hsp90 chaperone function which play important roles in growth, proliferation, survival, and apoptosis of cancer cells (Table 1). Hsp90 significant role in cancer treatment because of Hsp90 inhibition provide degradation of oncogenic client proteins. This significant function of Hsp90 has made it important target in anti-cancer drug development [3,6,7].

Pathways Client Proteins
Apoptosis Akt,Rip,p53,Survivin, Apaf-1,Bcl2, IGF-IR
Growth signals EGFR, Raf, Bcr-Abl, ErbB-2, Src, Akt,
Metastable signals MMP-2, c-MET, HIF-1-α
Angiogenesis VEGFR, HIF1,Akt, FAK, Src
Anti-growth signals Plk-1,Cdk4,Cdk6, Myt-1,cyclin D

Table 1: Important oncogenic client proteins.

Cancer is a genetic disease that is the leading cause of death worldwide and is defined with six hallmarks by Hanahan and Weinberg [8]. New drug development efforts have been continued for cancer treatment. Cancer is a complex disease, some tumors in advanced patients has substantial complexity and biological heterogeneity. For this reason, novel drugs must be developed and using Hsp90 key function in folding client proteins researchers design Hsp90 inhibitors [7,9,10].

Hsp90 inhibitors are two classes; N-terminal domain inhibitors and C-terminal domain inhibitors as shown in Table 2.

N-terminal inhibitors C-terminal inhibitors
Inhibitor Derived from Inhibitor Derived from
Tanespimycin
(17-AAG, KOS953)
Geldanamycin Chlorobiocin Novobiocin
Alvespimycin
(17-DMAG)
Geldanamycin Coumermycin Novobiocin
KF25706 Radicol    
KF29156 Radicol    
Cycloproparadicicol Radicol    
PU3 Purine    
PU24hFCl Purine    
PUS Purine    

Table 2: Hsp90 inhibitors.

Approximately fifteen Hsp90 inhibitors are in clinic studies in various cancer types. Many of these inhibitors bind to N-terminal domain ATP pocket that inhibit ATPase activity (Geldanamycin, radicicol, and purine derivates). But studies have directed to Cterminal domain as well due to toxic effect of N-terminal domain inhibitors. Hsp90 must be dimer form for carrying out the function. Cterminal inhibitors EGCG and novobiocin inhibit Hsp90 [2,11,12].

Drug designers try to find a better inhibitor for Hsp90 in terms of solubility and availability. Further, the researchers seek to find an inhibitor that will mimic the function of other complementary Heat Shock Proteins. A dual inhibitor that will block the function of Hsp70 will be an innovative form for this next generation drug candidates.

References

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Citation: Tutar L, Coskun KA, Tutar Y (2016) New Generation Cancer Drug Studies: Hsp90 Inhibitors. Single Cell Biol 5:e124.

Copyright: © 2016 Tutar L, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.