Editorial [Hot topic: Inhibition and Function of Heat Shock Proteins 70 and 90 (Guest Editor: Brian S. J. Blagg)]

Through the transcriptional/translational process, linear DNA is transformed into biologically active, three-dimensional proteins that provide the machinery necessary for cellular life. Elucidation of the processes involved in replicating and transcribing DNA led to some of the most important scientific discoveries during the 20th Century, however, the conformational maturation of linear information into tertiary and quaternary structures has only recently become the focus of scientific intensity. The conformational maturation of nascent polypeptides as well as the rematuration of denatured proteins is most often mediated by molecular chaperones. While many of these protein folders are constituitively active, a large class of proteins is induced upon sensing environmental stress such as elevated temperature, which leads to induction of the heat shock response and increased levels of heat shock proteins (Hsp) Hsp27, Hsp40, Hsp70 and Hsp90. As a consequence of the cellular stresses encountered by a growing tumor, Hsp are also required for the survival of transformed cells and provide a mechanism by which mutant proteins can be folded into physiologically active structures. As the master regulator of the heat shock response and the facilitator of a large number of signaling proteins, Hsp90 has emerged as the primary chaperone target for the development of new anti-tumor agents. In this special issue of Current Topics in Medicinal Chemistry, entitled Inhibition and Function of Heat Shock Proteins 70 and 90, nine articles have been assembled to represent a summary of cutting-edge research aimed at further understanding Hsp inhibition and consequences thereof. Through the use of structural and computational biology, traditional and structure-based drug design strategies have been employed to produce a large number of inhibitory scaffolds that disrupt the protein folding machinery. These small molecules act through a variety of mechanisms, which necessitated the development of new biochemical assays before commencement of clinical trials for these compounds. In this issue, a summary of these studies is provided along with emerging paradigms that are likely to result in additional clinical candidates. Jason Gestwicki produces a succinct account of the structure, function, and inhibition of the 70 kDa heat shock protein, Hsp70. Although required for the assembly of many Hsp90 heteroprotein complexes, Hsp70 has recently and independently garnered the attention as a new target for chaperone inhibition and the potential treatment of cancer and/or neurodegenerative disorders. Some of the most significant advances made toward chaperone inhibition have resulted from solution of their threedimensional structures. Chris Prodromou provides a thorough account of these advances and explains how these structures implicate potential new targets within the protein that can be focused upon to achieve selective inhibition/disruption of heteroprotein complex formation. The result of which may provide small molecules that manifest greater differential selectivity, or perhaps those that exhibit minimal toxicity. Gennady Verkhiver provides an exemplary overview of computational approaches used to develop inhibitors of the Hsp90 protein folding machinery. In addition, the Verkhiver review extends upon the solid state structures and sheds light on the potential role intermediate complexes may play in the protein folding process mediated by Hsp90 and its cohorts. The first inhibitor of the Hsp90 N-terminal ATP-binding pocket identified was geldanamycin, of which many derivatives have been produced, and few have entered clinical trials. James Porter gives a historical perspective on the geldanamycin scaffold and its utility for the development of improved Hsp90 inhibitors, ranging from the discovery of 17-AAG through the most recent derivative to enter clinical trials, IPI-504. Another class of natural products investigated for inhibition of the Nterminal nucleotide binding site is based on the resorcinolic acid lactones, as carefully reviewed by Nicolas Winssinger and colleagues. In an effort to circumvent undesired effects manifested by both geldanamycin and radicicol, several new series of compounds have been examined and developed that contain the resorcinol moiety as a key mediator of essential hydrogenbonding interactions. Various conformational constraints placed into the macrocyclic lactone have resulted in promising new scaffolds that exhibit potent Hsp90 inhibitory activities. The first structure-based drug design approach toward inhibition of Hsp90 resulted in the production of the purine-scaffold class of inhibitors. As detailed by Gabriela Chiosis, this molecular scaffold can be easily diversified, while maintaining selective inhibition of Hsp90. In fact, a member of the purine class of Hsp90 inhibitors was placed into clinical trials for the treatment of cancer. A summary of these developments is provided in this article. In contrast to inhibition of the Hsp90 N-terminal ATP-binding site, a number of alternative binding motifs have emerged in recent years. As summarized by Gary Brandt and Brian Blagg, the Hsp90 C-terminal nucleotide binding site and the Cdc37 binding motif have become particularly attractive regions for the development of small molecules that inhibit Hsp90, but through mechanisms of action that vary greatly from N-terminal inhibition. Several high-throughput screening (HTS) assays and biochemical techniques were required to identify and develop new scaffolds for Hsp90 inhibition. Robert Matts provides a thorough overview and detailed summary of these HTS assays as well as an in depth analysis of the biochemical tools that were developed in an effort to differentiate the mechanisms by which various Hsp90 inhibitors function. Without doubt, the most important outcome for any anti-cancer research program is the clinical result. Len Neckers, who pioneered many of the Hsp90 investigations and discovered the first Hsp90 inhibitor to enter clinical trials, 17-AAG, provides a detailed account of the molecules undergoing clinical evaluation. Furthermore, issues and complications arising from these studies are outlined as considerations for future clinical investigations. As one peruses this issue, it is hoped that the importance of chaperone inhibition is clearly stated as a new and attractive target not only for the development of anti-cancer agents, but also, neurodegenerative diseases. Significant advances toward the understanding of Hsp90 function have led to the identification of various disease states that could benefit from Hsp modulation. Although much of the research to date has focused on cancer, new disease states have been identified and some of which have already been sought after in clinical trials with the use of Hsp90 inhibitors. Thus, in spite of the significant advances made during the past 20 years of Hsp research, the field remains in its infancy.