HSP INHIBITORS AGAINST PROTEIN FOLDING

by Selleckchem | Mar 19 2012

Introduction: Cellular Quality Assurance

The network of chemical reactions linked to the mechanisms behind cellular growth, proliferation and differentiation are complex. Referred to as biochemical pathways these mechanisms operate on some simple principles starting with the receipt of a message from the host system to the cell itself. The pathway system can be likened to a production line facility with the product being a normal health cell. So mechanisms exists for stock piling of raw materials, for the synthesis of component parts, for the recycling of waste materials, for the removal of unwelcome molecules, quality assurance and final product viability. One the key aspects of cellular growth is the delicacy of the whole process, it does not take much to drive a mechanism off balance and produce a faulty product, to ensure quality under stress induced conditions a series of proteins exist referred to as Heat Shock Proteins that assess the quality of proteins being constructed for cell growth purposes. (1, 2)

There are two key HSP´s that govern this mechanism; HSP70 and HSP90 where the number refers to the mass of the protein when examined under western blot. In addition to these two key regulators there are a series of smaller proteins, which when complexed to either HSP70 or HSP90 dictate which way the mechanism goes. This simple pathway has two end points via HSP70 to degradation and via HSP90 to successful protein folding. The mechanism of action for this pathway is via the inhibition of either HSP70 (inducing cellular growth) or by inhibition of HSP90 (inducing cellular death) and a series of naturally occurring molecules exist to perform this task (3, 4). In terms of metabolic disorders often, the proteins supervised by HSP90 in correct folding activities are actually mutated forms linked to the progression of tumors, degenerative neurological disorders (5) or viral infections (6). Hence, HSP90 inhibition was considered to be an ideal choice as a chemotherapy target. The development of a HSP90 selective inhibitor was achieved by looking to nature and examining the binding domain related to HSP90 activity. HSP90 pathway inhibitors were determined to relate to nucleosides and be able to conform to a specific binding conformation not normally associated with nucleosides themselves. From this information two HSP90 specific inhibitors were developed, Geldanamycin and Radicicol, from these two structures and the HSP90 structure of the binding domain all-current generations of HSP90 inhibitors have been developed. (7, 8)

HSP90 INHIBITORS:

The two natural products Geldanamycin and Radicicol are HSP90 antagonists and appear to work by binding irreversibly to the ATP binding pocket of the complex formed by HSP90 and a client protein. The irreversible binding prevents the client protein from leaving the HSP90 complex, which means it never achieves an active conformation. Under such circumstances the protein is in non-conformance with checks placed on it hence it would be mark for destruction and pass down the HSP70 section of the pathway (9). Second generation HSP90 inhibitor drugs follow similar patterns to Geldanamycin and Radicicol but have significantly less toxicity. In recent years it has been found that HSP90 can also be found in the mitochondria and this is functional different to the cytosolic HSP90. A class of molecule that inhibits mitochondrial HSP90 are called the Gamtinibs and are based on the structure of 17 AAG (a 2^nd generation derivative of Geldanamycin) in combination with a mitochondrial recognition moiety. This series of molecules have demonstrated specific targeting to cancer cells and have been observed to induce apoptosis in xenografts. HSP90 kinase inhibitors are still in the testing phase with Geldanamycin and Radicicol demonstrating strong inhibition of HSP90 but also showing extreme toxicity and the ability to cause liver damage. Hence, 2^nd generation inhibitors such 17AAG Alvesoimycin and KW2478 have been systematically developed to exhibit strong potency but less toxicity. To buy HSP90 inhibitor any researcher can access online biochemical companies and for a reasonable price purchase any one of many different molecules. Utilizing inihibition on a regular basis, paving the way for effective treatment profiles in the near future.(10)

Clinical Status:

Clinically only limited success has been achieved with HSP90 inhibitors to date (11). The first two products found Geldanamycin and Radicicol proved to be far to toxic for clinical patients in HSP90 inhibitor in clinical trials. While 1^st generation molecules 17-AAG and 17 DMG proved more successful but still exhibit a poor toxicity profile. The 2^nd generation molecules are still in preclinical testing and have yet to be clinically proven; molecules such as NVP-AUY922, Celastrol, CUDC-305, STA-9090 (12), Macbecin, SNX-2112, Gedunin, PU-H71 and Derrubone.(13)

Reference List

(1) Petrikaite V, Matulis D. Binding of natural and synthetic inhibitors to human heat shock protein 90 and their clinical application. Medicina (Kaunas ) 2011;47:413-20.

(2) Lu X, Xiao L, Wang L, Ruden DM. Hsp90 inhibitors and drug resistance in cancer: The potential benefits of combination therapies of Hsp90 inhibitors and other anti-cancer drugs. Biochem Pharmacol 2011.

(3) Wang RE. Targeting heat shock proteins 70/90 and proteasome for cancer therapy. Curr Med Chem 2011;18:4250-64.

(4) Yamaki H, Nakajima M, Shimotohno KW, Tanaka N. Molecular basis for the actions of Hsp90 inhibitors and cancer therapy. J Antibiot (Tokyo) 2011;64:635-44.

(5) Salminen A, Ojala J, Kaarniranta K, Hiltunen M, Soininen H. Hsp90 regulates tau pathology through co-chaperone complexes in Alzheimer's disease. Prog Neurobiol 2011;93:99-110.

(6) Travers J, Sharp S, Workman P. HSP90 inhibition: two-pronged exploitation of cancer dependencies. Drug Discov Today 2011.

(7) Whitesell L, Lin NU. HSP90 as a platform for the assembly of more effective cancer chemotherapy. Biochim Biophys Acta 2011.

(8) Neckers L, Workman P. Hsp90 molecular chaperone inhibitors: are we there yet? Clin Cancer Res 2012;18:64-76.

(9) Staufer K, Stoeltzing O. Implication of heat shock protein 90 (HSP90) in tumor angiogenesis: a molecular target for anti-angiogenic therapy? Curr Cancer Drug Targets 2010;10:890-7.

(10) Messaoudi S, Peyrat JF, Brion JD, Alami M. Heat-shock protein 90 inhibitors as antitumor agents: a survey of the literature from 2005 to 2010. Expert Opin Ther Pat 2011;21:1501-42.

(11) Khalil AA, Kabapy NF, Deraz SF, Smith C. Heat shock proteins in oncology: Diagnostic biomarkers or therapeutic targets? Biochim Biophys Acta 2011;1816:89-104.

(12) Wang Y, Trepel JB, Neckers LM, Giaccone G. STA-9090, a small-molecule Hsp90 inhibitor for the potential treatment of cancer. Curr Opin Investig Drugs 2010;11:1466-76.

(13) Jhaveri K, Taldone T, Modi S, Chiosis G. Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers. Biochim Biophys Acta 2011.

Cat.No.	Product Name	Information
S2713	Geldanamycin	Geldanamycin is a natural existing HSP90 inhibitor with K_d of 1.2 μM, specifically disrupts glucocorticoid receptor (GR)/HSP association. Geldanamycin attenuates virus infection-induced ALI (acute lung injury)/ARDS (acute respiratory distress syndrome) by reducing the host's inflammatory responses.
S1141	Tanespimycin (17-AAG)	Tanespimycin (17-AAG, CP127374, NSC-330507, KOS 953) is a potent HSP90 inhibitor with IC50 of 5 nM in a cell-free assay, having a 100-fold higher binding affinity for HSP90 derived from tumour cells than HSP90 from normal cells. Tanespimycin (17-AAG) induces apoptosis, necrosis, autophagy and mitophagy. Phase 3.