Inhibitors of HSP90 and other chaperones for the treatment of cancer

Molecular chaperones are proteins that ensure the appropriate folding, stability and function of other proteins in the cell. There is increasing evidence that molecular chaperones are not only important in normal cell homeostasis and response to stresses, such as heat shock, but can also be involved in disease pathology. in particular, HSP90 has emerged as an important potential drug target in oncology. This is because it is essential for the stability of a long list of 'client proteins', including ErbB2/human epithelial growth factor receptor (HER)2, Raf-1, Akt/protein kinase B (PKB), Polo-1, Met, mutant p53 and human telomerase reverse transcriptase (hTERT), as well as the oestrogen and androgen receptor. Inhibition of HSP90 leads to depletion of these oncogenic clients by the ubiquitin proteasome pathway, thereby providing a simultaneous combinatorial attack on all of the hallmark phenotypic traits of cancer cells. Because of the rapid progress made, this review focuses on the patents dealing with the discovery and application of small molecule inhibitors of HSP90, although limited coverage of other applications in the area of HSP90 and additional chaperones is also included. Pioneering work with natural products, namely geldanamycin and related ansamycin antibiotics together with radicicol macrocycle derivatives, established the therapeutic potential of inhibiting the essential N-terminal ATPase of HSP90 by competing at the nucleotide binding site. A geldanamycin analogue, 17-(desmethoxy), 17-allylamino geldanamycin (17AAG), is completing Phase I clinical trials with promising initial results. The use of high-throughput screening and rational design based on X-ray crystal structures of HSP90 has led to the discovery of small molecule HSP90 inhibitors based on purine and pyrazole scaffolds. The continued progression of these various compound classes into clinical trials should help to establish proof of concept for inhibition of HSP90 as a Viable therapeutic approach for the treatment of cancer and potentially other diseases. This would in turn validate protein folding as a strategy for drug development and encourage additional chaperones to be explored as molecular targets.