emphasis mine......
Curr Cancer Drug Targets. 2003 Oct;3(5):371-6.
Development of purine-scaffold small molecule inhibitors of hsp90.
Chiosis G, Lucas B, Huezo H, Solit D, Basso A, Rosen N.
Department of Medicine and Cell Biology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021, USA. chiosisg@mskcc.org
The Hsp90 chaperones play a key role in regulating the physiology of cells exposed to environmental stress and in maintaining the malignant phenotype in tumor cells. Agents that interfere with the function of the chaperone may thus be beneficial in the treatment of cancers. The ansamycins (geldanamycin and herbimycin) and the unrelated natural product radicicol were found to bind to the N-terminal pocket of Hsp90 and inhibit its function. However, translation of these compounds to the clinic was impeded by stability and hepatoxicity issues. 17AAG, a derivative of geldanamycin, was found to be less hepatotoxic and is currently undergoing Phase I clinical trial. Unfortunately, 17AAG is insoluble, difficult to formulate and it is not yet clear if therapeutically effective doses can be administered without escalating non-Hsp90 associated toxicities. Additionally, for reasons not yet completely understood, a subset of tumor cells are insensitive to the action of the drug. The development of novel agents that lack the drawbacks of the natural products is thus necessary. Here we present an overview of such efforts with focus on a new class of purine-scaffold Hsp90 inhibitors developed by rational design.
Curr Cancer Drug Targets. 2003 Oct;3(5):297-300.
Overview: translating hsp90 biology into hsp90 drugs.
Workman P.
Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey SM2 5NG UK. Paul.Workman@icr.ac.uk
The Hsp90 molecular chaperone has emerged as one of the most exciting targets for cancer drug development. Hsp90 is overexpressed in many malignancies, very likely as a result of the stress that is induced both by the hostile cancer microenvironment and also by the mutation and abberant expression of oncoproteins. A particularly attractive feature of Hsp90 as a cancer drug target is that it is required for the conformational stability and function of a wide range of oncogenic 'client' proteins, including c-Raf-1, Cdk4, ErbB2, mutant p53, c-Met, Polo-1 and telomerase hTERT. Inhibition of Hsp90 should therefore block multiple mission critical oncogenic pathways in the cancer cell, leading to inhibition of all the hallmark traits of malignancy. This combinatorial blockade of oncogenic targets should give rise to board spectrum antitumour activity across multiple cancer types. The 'druggability' of Hsp90 was confirmed by the discovery that the natural products geldanamycin and radicicol, which have anticancer activity, exert their biological effects by inhibiting the essential ATPase activity associated with the N-terminal domain of the protein. The first-in-class Hsp90 inhibitor has entered clinical trial and provided proof of concept that Hsp90 can be inhibited and clinical benefit seen at non-toxic doses. Further development is underway and a related analogue 17DMAG also shows promise in preclinical models. In addition, novel Hsp90 inhibitors have been identified using methods such as high throughput screening and x-ray crystallography. The opportunities and challenges involved in translating the fast moving biology of Hsp90 into patient benefit is discussed. |
