Hsp90 inhibitors: Small molecules that transform the Hsp90 protein folding machinery into a catalyst for protein degradation

The 90 kDa heat shock proteins (Hsp90) are responsible for the conformational maturation of nascent polypeptides and the renaturation of denatured proteins. In transformed cells, numerous mutated and overexpresscd proteins rely on the Hsp90 protein folding machinery for tumor progression. The Hsp90-mediated protein folding process is dependent upon ATP. and when inhibitors of ATP are present, the Hsp90 machinery is unable to fold client proteins into their biologically active form. which results in the degradation of protein substrates via the ubiquitin-proteasome pathway. Consequently, Hsp90 has evolved into a promising anti-cancer target because multiple oncogenic proteins can be simultaneously degraded as a consequence of Hsp90 inhibition. This review serves to explain the Hsp90 protein folding process, the impact of Hsp90 inhibition, the identification of natural product inhibitors, and the development of rationally designed inhibitors of the Hsp90 protein folding machinery. (c) 2005 Wiley Periodicals, Inc.