The Development of Organelle-localized Hsp90 Isoform-selective Inhibitors

Abstract

Molecular chaperones are responsible for the maturation of nascent polypeptides and the re-maturation of denatured proteins. One chaperone family that has emerged as an attractive therapeutic target is the 90 kDa heat shock proteins (Hsp90). Hsp90 is responsible for the maturation of proteins associated with all ten hallmarks of cancer, and its inhibition results in a multidirectional attack on cancer. More than seventeen small molecule inhibitors have entered clinical trials; however, concerns have risen due to toxicities, dosing and scheduling issues, and lack of efficacy as a single agent. Therefore, alternative strategies for Hsp90 inhibition are needed to take advantage of the unique biological role of Hsp90. All of the molecules evaluated in clinical trials exhibit pan-Hsp90 inhibition and target all four Hsp90 isoforms with similar affinities. Humans express four different Hsp90 isoforms: Hsp90α and Hsp90β reside in the cytosol, Grp94 is localized to the endoplasmic reticulum, and TRAP1 is found in the mitochondria. Emerging evidence suggests that each Hsp90 isoform plays a unique role in cancer progression. Therefore, to further study the individual roles of each isoform, the development of Hsp90 isoform-selective inhibitors is highly desirable. However, the development of such inhibitors is hindered by the fact that the N-terminal ATP-binding pocket is 85% identical among all four isoforms. Described herein is the development of isoform-selective inhibitors of the ER- and mitochondria-localized Hsp90 isoforms, Grp94 and TRAP1, respectively. Grp94-selective inhibitors were evaluated in models of myocilin-associated open angle glaucoma, cancer metastasis, and multiple myeloma. TRAP1-selective inhibitors were evaluated for their ability to induce apoptosis in cancer cells. These isoform-selective inhibitors will serve as invaluable tools to continue to study the roles played by these isoforms in cancer as well as other indications.