Targeting Hsp90: small-molecule inhibitors and their clinical development

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The Hsp90 multichaperone complex has important roles in the development and progression of malignant transformation. Several small-molecule inhibitors of Hsp90 of diverse chemotypes have shown potent antitumor activity in a wide-range of malignancies, and are currently in clinical or late-stage preclinical investigation. This review intends to update the reader on advances made over the past two years in the clinical development of Hsp90 inhibitors in advanced cancers. It will refer to the two 17-AAG formulations, tanespimycin and IPI-504, and to synthetic small molecules, among which are the purine-scaffold Hsp90 inhibitor CNF2024/BIIB021, the isoxazole derivative VER-52296/NVP-AUY922, and the carbazol-4-one benzamide derivative SNX-5422, and will present our current knowledge on their clinical performance.

Introduction

The Hsp90 superchaperone complex has wide-ranging functions that result from the ability of this sophisticated machinery to assist in the folding and function of a variety of oncogenic ‘client proteins’ [1, 2]. In this sense, multiple proteins involved in cell-specific oncogenic processes have been shown to be tightly regulated by the binding of the Hsp90 machinery. These include BCR-ABL in the chronic myelogenous leukemia (CML) [3], nucleophosmin–anaplastic lymphoma kinase (NPM–ALK) in lymphomas [4], mutated FLT3 in acute myeloid leukemia [5], EGFR harboring kinase mutations in nonsmall cell lung cancer (NSCLC) [6], the zeta-associated protein of 70 kDa (ZAP-70) as expressed in patients with aggressive chronic lymphocytic leukemia (CLL) [7], mutant B-Raf in melanoma [8], human epidermal growth factor receptor 2 (HER2) in HER2-overexpressing breast cancer [9], mutant c-Kit in gastrointestinal stromal tumors (GIST) [10], and activated Akt in small cell lung carcinoma [11], to list a few. It is now accepted that at the phenotypic level, the Hsp90 machinery serves as a biochemical buffer for the numerous cancer-specific lesions that are characteristic of diverse tumors. Pharmacologic inhibition of Hsp90 by structurally diverse small molecules destabilizes the cancer cell's aberrant protein subset, leading to protein degradation by the 26S proteasome [12]. Selective depletion of the cancer cell's malignancy driving molecules results in growth arrest, apoptosis, and renders cells vulnerable to the actions of chemotherapeutic interventions that otherwise afford limited benefit [1, 2]. Moreover, cancer cells are selectively sensitive to pharmacologic Hsp90 inhibitors, and administration of these agents to multiple cancer animal models results in significant antitumor effects associated mostly with little or no target-associated toxicities [1, 2, 13].

The successful validation of Hsp90 as a target in cancer through the use of pharmacologic agents has catalyzed the development of these small-molecule tools into anticancer therapeutics [14]. This review will focus on advances made over the past two years in the clinical translation and development of several Hsp90 inhibitor chemotypes.

Section snippets

Geldanamycin-based Hsp90 inhibitors

The first Hsp90 inhibitor to enter clinic was the geldanamycin (GM) derivative 17-allylamino-17-desmethoxy-geldanamycin (17-AAG) (Figure 1). Initial clinical evaluation of 17-AAG was of limited success, with hints of activity demonstrated in melanoma, where stable disease (SD) was reported [14]. Improvements in this drug's formulation and delivery have led to more encouraging results in several difficult-to-treat patient populations. Kosan Biosciences has developed both a Cremophor-containing

Synthetic Hsp90 inhibitors

Novel synthetic Hsp90 inhibitors based on diverse chemical scaffolds have been developed, and several are currently undergoing Phase I/II clinical evaluation in cancers. These are reported to generally have an improved pharmacologic profile when compared to 17-AAG, especially with regard to their availability through synthesis, evasion of multidrug resistance (MDR)-mediated efflux, metabolic stability, water solubility and ease of administration, and retained biological activity over a wider

Conclusions

In conclusion, several Hsp90 inhibitors have now entered clinical evaluation. One lesson from these trials is that the more we have learned how to administer these agents, the better the clinical outcomes have become. It is now expected that through new formulations of 17-AAG and through the novel synthetic Hsp90 inhibitors, also orally administrable, it will be possible to more favorably modulate the schedule and dose these inhibitors are given. It is the hope that these advances will increase

Acknowledgements

This work was supported partly by the Susan G. Komen Breast Cancer Foundation, the SynCure Cancer Research Foundation, the Clinical & Translational Science Center of Weill Cornel Medical College, Geoffrey Beene Cancer Research Center of Memorial Sloan-Kettering Cancer Center (MSKCC), the Byrne Fund of MSKCC, the Manhasset Women's Coalition Against Breast Cancer and by generous donations from the Mr William H Goodwin and Mrs Alice Goodwin and the Commonwealth Cancer Foundation for Research and

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