hsp90 as a therapeutic target in endocrinology: current evidence

Thomas Ratajczak,1,2 Bryan Kenneth Ward,1,2 John Peter Walsh,2,3 Carmel Cluning1,2 1Laboratory for Molecular Endocrinology, Harry Perkins Institute of Medical Research and The UWA Centre for Medical Research, The University of Western Australia, 2Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Hospital Avenue, 3School of Medicine and Pharmacology, The University of Western Australia, Nedlands, WA, Australia Abstract: The ability of heat shock protein 90 (Hsp90) to modulate many growth and signaling pathways simultaneously makes it an attractive target in the field of cancer therapeutics and provided the initial impetus for significant efforts over the past decade to identify Hsp90 inhibitors, several of which are now showing promise in the clinic for cancer treatment. The four known human Hsp90 members are compartmentalized: Hsp90α and ß in the cytoplasm, GRP94 in the endoplasmic reticulum, and TRAP1 in the mitochondrial matrix. While these isoforms share a similar N-terminal domain adenosine triphosphate-binding pocket, structural variations allow unique interactions for inhibitors targeting this binding site, providing an avenue for the development of paralog-selective drugs with different biological effects applicable therapeutically to a wide range of diseases. At the same time, the conformational flexibility of the Hsp90 molecular chaperone has unveiled multiple small-molecule target sites within all subdomains of the protein, greatly expanding opportunities for viable drug development. This review summarizes the function, expression, and clinical significance of the Hsp90 isoforms and elaborates on the inhibitors and modulators that impact Hsp90 chaperone activity. Finally, the review focuses on the therapeutic utility of a range of Hsp90-modulating agents in the treatment of specific diseases associated with the endocrine system. Keywords: heat shock protein 90, GRP94, TRAP1, Hsp90 inhibitors, endocrine disorders