Editorial [ Molecular Chaperones as Targets in Medicinal Chemistry and Drug Discovery Guest Editor: Dr. Gabriela Chiosis ]

Contained in this issue of CTMC are several papers that highlight recent contributions to the development of small molecules that target the molecular chaperones Hsp90 and Hsp70, the use of these molecules to understand the clinical significance of modulating these chaperones’ function, and finally, progress in the translation of such agents to clinic. Hsp90 is a chaperone with important roles in maintaining transformation and in elevating the survival and growth potential of cancer cells. However, in addition to its roles in facilitating the transformed phenotype, Hsp90 serves several functions in normal cell homeostasis. Even under non-stressed conditions, Hsp90 comprises as much as 1-2% of total cellular protein content, and this amount increases only about two to three fold under stress. In eukaryotes, constitutive genetic knockout of Hsp90 is lethal. Thus, until the discovery of pharmacological agents that inhibit Hsp90 function, it has not become apparent that the chaperone may be a target in disease. Len Neckers begins this CTMC issue by providing a description of the biology of Hsp90 and how natural product derivatives such as geldanamycin, radicicol and novobiocin have been used to understand both the structure and biological significance of Hsp90 in cancer. Further, Brian Blagg and his colleagues discuss structure-activity relationship investigations in the natural product Hsp90 inhibitor classes and present several synthetic efforts directed at both improving the selectivity and pharmacological profiles of these agents. In spite of the usefulness of these natural products as proof-of-principle compounds, their clinical use has been encumbered by their less than desirable pharmacological profiles. These drawbacks have prompted for the discovery of novel Hsp90 inhibitors. Several synthetic second generation Hsp90 inhibitors are now in late preclinical development, while others are going through early stages of discovery. These new compounds hold the promise of better drug-like properties and of improved pharmacological profiles. Two such classes are discussed in this issue. First, Gabriela Chiosis provides the rationale behind the discovery and development of the first synthetic class of Hsp90 inhibitors, the purine-scaffold series. The biological activities, selectivity for tumor cells and tumor retention profiles of these inhibitors are further discussed in this review. Ted McDonald and his colleagues from the Institute of Cancer Research, UK and from Vernalis Ltd. describe the identification by high-throughput screening of pyrazole-based Hsp90 inhibitors and discuss the optimization of compounds based on the pyrazole scaffold by structure-based design, emphasizing in particular the value of X-ray crystallography. Further, David Solit and Neal Rosen update the reader on efforts directed at the rational translation of Hsp90 inhibitors in cancer treatment and on progress in the ongoing clinical trials with these agents. Finally, Jeffrey Brodsky and Gabriela Chiosis will introduce another chaperone with important biological functions, Hsp70. In this review, the authors will summarize the structural and functional characteristics of Hsp70 chaperones, and discuss their roles in cellular physiology. They will also review the recent discovery of small molecules that alter Hsp70 expression and function, and further discuss their possible application as treatments of specific cancers, infections, and protein conformational diseases.