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Review
. 2009;9(15):1447-61.
doi: 10.2174/156802609789895683.

Alternate strategies of Hsp90 modulation for the treatment of cancer and other diseases

Gary E L Brandt  1 , Brian S J Blagg
Affiliations
Review

Alternate strategies of Hsp90 modulation for the treatment of cancer and other diseases

Gary E L Brandt et al. Curr Top Med Chem. 2009.

Abstract

The 90 kDa heat shock protein (Hsp90) has become a validated target for the development of anti-cancer agents. Several Hsp90 inhibitors are currently under clinical trial investigation for the treatment of cancer. All of these agents inhibit Hsp90's protein folding activity by binding to the N-terminal ATP binding site of the Hsp90 molecular chaperone. Administration of these investigational drugs elicits induction of the heat shock response, or the overexpression of several Hsps, which exhibit antiapoptotic and pro-survival effects that may complicate the application of these inhibitors. To circumvent this issue, alternate mechanisms for Hsp90 inhibition that do not elicit the heat shock response have been identified and pursued. After providing background on the structure, function, and mechanism of the Hsp90 protein folding machinery, this review describes several mechanisms of Hsp90 modulation via small molecules that do not induce the heat shock response.

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Figures

Fig. 1
Fig. 1
Representative examples of natural product and synthetic inhibitors of the Hsp90 protein folding machinery.
Fig. 2
Fig. 2
Pictorial representation of the 3 structural domains of Hsp90.
Fig. 3
Fig. 3
Hsp90 protein folding process for protein kinase clients. 1–2) After first associating with Hsp70, Hsp40, and then Cdc37, nascent polypeptide is recruited to Hsp90 by HOP and Cdc37, both of which inhibit ATPase activity. 2–3) Peptide is loaded onto Hsp90 and HOP/Hsp70/Hsp40 protein complex is replaced by FKBP52 (or other immunophilin) 3–4) p23 is recruited to the heteroprotein complex, and N-terminal dimerization ocurrs. 4–5) Aha1 binds Hsp90 middle domain, whereupon client folding process takes place and ATP is hydrolysed to ADP. 5–1) After ATP hydrolysis, the molecular clamp is forced open, mature kinase client is released, and ADP is replaced by ATP so that the catalytic cycle may repeat.
Fig. 4
Fig. 4
Examples of Hsp90 N-terminal inhibitors in clinical trials.
Fig. 5
Fig. 5
A4, induces heat shock response at concentrations as low as 1 nM, however exhibits no anti-proliferative activity at 100 µM.
Fig. 6
Fig. 6
The transformation of NB, a DNA gyrase B inhibitor (DNA gyrase IC50 of 1 µM, Hsp90 IC50 of ∼700 µM), into lead compound DHN2 (DNA gyrase IC50 of >500 µM, Hsp90 IC50 of 1 µM) for the development of novel C-terminal inhibitors. Dashed boxes highlight regions where removal of functionality lead to increased potency.
Fig. 7
Fig. 7
Compound 46, incorporating the indole moiety as a substitute for the prenylated benzamide increased potency of DHN2 lead from 1 µM to compound 46 with an IC50 of 170 nM in HCT-116 colon cancer cell line.
Fig. 8
Fig. 8
Compound 5g, a simplified denoviosylated NB analog that inhibits Hsp90 and manifests antiproliferative activity with an IC50 of 35 µM.
Fig. 9
Fig. 9
SAR developments garnered from coumarin substituent effects investigated by Donnely et al. Methoxy substituent at R1 increases activity, Bulky alkoxy substituents tolerable at R2, substitution at R3 decreases Hsp90 inhibitory activity, most active side chain is indole at R4.
Fig. 10
Fig. 10
Celastrol, a known Hsp90 inhibitor that disrupts the Cdc37/Hsp90 interaction, and other potential inhibitors gedunin, gamendazole, and the gedunin derivatives 7-desacetylcarbamategedunin and 7-oxogedunin.
Fig. 11
Fig. 11
Compounds identified through AlphaScreen HTS to inhibit Hsp90/Hop interaction by binding to the TPR domain of Hop.
Fig. 12
Fig. 12
Examples of HDAC inhibitors that manifest Hsp90-dependent client protein degradation.
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