Designing Drugs Against Hsp90 for Cancer Therapy

Heat shock protein 90 (Hsp90) is a molecular chaperone exploited by cancer cells to aid the function of numerous oncoproteins. The recognition of Hsp90 as a critical facilitator for oncogene addiction and survival of the cancer cell has opened a promising new niche for cancer treatment. The serendipitous discovery that the broad spectrum anticancer activity of the natural products geldanamycin (GM) and radicicol (RD) was a result of inhibition of Hsp90 resulted in the development of improved derivatives of these natural products. One of these was 17 allylaminogeldanamycin (17-AAG), a closely related analog of GM, and was in fact the first Hsp90 inhibitor to enter the clinic. However, GM and its analogs suffer from poor “drug-like” properties and this served as a strong impetus for the development of novel synthetic Hsp90 inhibitors. These efforts resulted in the development of numerous potent synthetic small molecule inhibitors with significant scaffold diversity as well as superior pharmacokinetic and toxicity profile to have entered clinical trials. This review highlights the drug discovery efforts pertaining to the development of the first and second-generation Hsp90 inhibitors, and also gleans over their individual promise as clinical agents for anticancer therapy.