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A New Generation of Isoform Selective Hsp90 Inhibitors: Targeting the Cytosolic Hsp90 Isoforms
Mishra, Sanket
Mishra, Sanket
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Abstract
Heat shock protein 90 kDa (Hsp90) is a member of the molecular chaperone family of proteins that processes newly synthesized polypeptides into their three-dimensional and biologically active form. In addition, Hsp90 assists in the stabilization, trafficking and refolding of denatured proteins. Many Hsp90-dependent proteins are critical to the pathogenesis of cancer, neurodegeneration and/or viral infection. As a result, Hsp90 has garnered attention as a chemotherapeutic target and has resulted in the development of more than 17 Hsp90 inhibitors that that have been evaluated in clinical trials. However, these inhibitors exhibit pan-inhibitory activity against all four Hsp90 isoforms: Hsp90alpha, Hsp90beta, Grp94 and Trap1, which results in various side effects, including, hepatotoxicity, cardiotoxicity, and renal toxicity. Therefore, the development of isoform-selective Hsp90 inhibitors has been proposed to delineate the contribution of each Hsp90 isoform towards these toxicities. The cytosolic Hsp90 isoforms, alpha and beta modulate the activity of numerous Hsp90-dependent proteins that regulate cancer progression. Hydrolysis of ATP by the N-terminal nucleoside-binding site provides the energy required for the maturation of client protein substrates, and all four Hsp90 isoforms share 85% identity within this region. Between cytosolic Hsp90 isoforms (alpha and beta), the N-terminal ATP-binding site exhibits 95 % identity. As a result, the design of inhibitors that selectively target individual cytosolic Hsp90 isoforms has been challenging. Described herein is the development of Hsp90alpha- and Hsp90beta-selective inhibitors using a structure-based approach that has produced compounds that exhibit both high selectivity and affinity. The efficacy of these inhibitors has been evaluated against an array of cancer cell lines and revealed an Hsp90 isoform-dependent cancer profile.
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Date
2018-05-31
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Publisher
University of Kansas
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Keywords
Pharmaceutical sciences, Anticancer, Drug Discovery, Hsp90, Medicinal Chemistry, Structure-based Design