Inhibitors of the HSP90 chaperone pathway
Paul Workman
The Institute of Cancer Research, Sutton, UK
The molecular chaperone HSP90 has emerged as an exciting new drug target. A major advantage is that inhibition of HSP90 results in simultaneous combinatorial depletion of multiple oncogenic ‘client’ proteins, leading to parallel blockade of many cancer-causing pathways and the antagonism of all of the hallmark features of malignancy. Therapeutic selectivity is achieved by exploiting both the dependence of cancer cells on oncogenic clients and also the stressed state of malignant cells (Workman et al Ann NY Acad Sci 1113 202-216 2007). The combinatorial effects of HSP90 inhibitors should make the development of resistance much more difficult than is the case for agents having more limited effects, and recent results from our lab support this view (Gaspar, Pacey et al, submitted).
The HSP90 field was opened up by research on the natural product HSP90 inhibitors geldanamycin and radicicol. These agents not only provided the basis for several drugs that are in clinical development, but were also important chemical tools to help understand HSP90 biology. The geldanamycin inhibitors 17-AAG (tanespimicin), 17-DMAG (alvespimicin) and the 17-DMAG hydroquinone (IPI-504) have all entered clinical trials. The first-in-class HSP90 drug, 17-AAG, provided proof of concept for HSP90 inhibition in the tumor tissue of patients at well tolerated doses (Banerji et al J Clin Oncol 23 4152-4161 2005); therapeutic activity has been seen with 17-AAG, for example in melanoma patients with KRAS and RAF mutations (Banerji et al Mol Cancer Ther 7 737-739) and in trastuzumab-resistant ERBB2-positive breast cancer patients. There is also potential in multiple myeloma through specific clients and exploitation of the unfolded protein response (Davenport et al Blood 110 2641-269 2007). New potentially sensitive tumour types are being defined based on dependence of key proteins and pathways on HSP90 (Workman and Powers Nat Chem Biol 3 455-457 2007).
Second generation, small molecule inhibitors have been developed using a combination of high throughput screening technologies and structure-based design (Sharp and Workman Adv Cancer Res 95:323-348 2006; Smith and Workman, Drug Discovery Today: Therapeutic Strategies, published on-line 3 April 2008). From the purine scaffold inhibitor class the orally active agent BIIB021 is now in clinical trials. The pyrazole/isoxazole class of synthetic small molecule inhibitors that we discovered contains the essential resorcinol unit also present in radicicol (Cheung et al Bioorg Med Chem Lett 15 3338-3343 2005) and NVP-AUY922, derived from this series, has entered clinical studies (Brough et al J Med Chem 51 196-218 2008; Eccles et al Cancer Res Cancer Res 68 2850-2860 2008). Other inhibitors show promise in preclinical and clinical development. The emerging new drugs illustrate the benefits of high-throughput compound library screening, structure-based design and chemical biology approaches. Opportunities and challenges for HSP90 inhibitors will be discussed, including use in combination with other agents, as in ovarian cancer with deregulated PI3 kinase signalling (Sain et al N Mol Cancer Ther 5 1197-1208 2006; Banerji et al Cancer Chemother Pharmacol Jan 10 2008 Epub ahead of print).
All of the current HSP90 drugs in the clinic act by blocking the essential nucleotide binding and ATPase activity required for chaperone function. Potential new approaches will be discussed, for example interference with cochaperone binding and function in the superchaperone complex. Our increasing understanding of the structure-function relationships for the HSP90 multichaperone complex provides the basis for new therapeutic approaches (Pearl, Prodromou and Workman, Biochem J 439-453 2008; Smith and Workman, Drug Discovery Today: Therapeutic Strategies, published on-line 3 April 2008). As an example, our recent studies have shown that silencing of the HSP90 ATPase-activating protein AHA1 decreases the activation but not the stability of HSP90 client proteins and increases the sensitivity of cancer cells to 17-AAG (Holmes et al Cancer Res 68 1187-1196 2008). Biomarkers for use with HSP90 inhibitors will be described, including those identified in our gene expression and proteomic profiling studies (Maloney et al Cancer Res 67 3239-3253 2007). Success with HS90 inhibitors has encouraged therapeutic targeting of other elements of the heat shock response that is regulated by HSF1 (Powers and Workman P FEBS Lett 581 3758-3769 2007; Workman and de Billy Nat Med 2007 13 1415-1417 2007).
Basic and translational research on HSP90 have been interwoven and mutually beneficial and this synergy has pointed to future directions to enhance our understanding of the structure and function of molecular chaperones and their exploitation in cancer and other diseases.
Acknowledgements
This research was supported by Cancer Research UK.
