Targeting the Hsp90-Cdc37-client protein interaction to disrupt Hsp90 chaperone machinery

Abstract

Heat shock protein 90 (Hsp90) is a critical molecular chaperone protein that regulates the folding, maturation, and stability of a wide variety of proteins. In recent years, the development of Hsp90-directed inhibitors has grown rapidly, and many of these inhibitors have entered clinical trials. In parallel, the functional dissection of the Hsp90 chaperone machinery has highlighted the activity disruption of Hsp90 co-chaperone as a potential target. With the roles of Hsp90 co-chaperones being elucidated, cell division cycle 37 (Cdc37), a ubiquitous co-chaperone of Hsp90 that directs the selective client proteins into the Hsp90 chaperone cycle, shows great promise. Moreover, the Hsp90-Cdc37-client interaction contributes to the regulation of cellular response and cellular growth and is more essential to tumor tissues than normal tissues. Herein, we discuss the current understanding of the clients of Hsp90-Cdc37, the interaction of Hsp90-Cdc37-client protein, and the therapeutic possibilities of targeting Hsp90-Cdc37-client protein interaction as a strategy to inhibit Hsp90 chaperone machinery to present new insights on alternative ways of inhibiting Hsp90 chaperone machinery.Electronic supplementary materialThe online version of this article (10.1186/s13045-018-0602-8) contains supplementary material, which is available to authorized users.

Puupehenone, a Marine-Sponge-Derived Sesquiterpene Quinone, Potentiates the Antifungal Drug Caspofungin by Disrupting Hsp90 Activity and the Cell Wall Integrity Pathway

“…This conclusion is based on the following lines of evidence: (i) the transcript and fitness profiles of PUUP were similar to those of Hsp90 inhibitors, (ii) PUUP activated Hsf1, (iii) PUUP blocked GR activation, (iv) yeast strains overexpressing genes encoding Hsp90 isoforms, an Hsp90 client protein, and an Hsp90 cochaperone were less sensitive to PUUP, and (v) molecular modeling predicted that PUUP binds to Hsp90 at a site involved in Hsp90-Cdc37 interactions. Given the limited number of compounds available which block the interaction between Hsp90 and Cdc37 (50), and with the availability of synthetic schemes for the synthesis of PUUP and its derivatives (51), PUUP will undoubtedly serve as an important pharmacological tool in the further characterization of Hsp90-Cdc37 interactions in pathogenic fungi and other eukaryotic organisms.…”

Structure, Function, and Regulation of the Hsp90 Machinery

“…Different inhibitors that disturb the Hsp90: Cdc37 complex, such as withaferin A (Yu et al 2010), celastrol (Zhang et al 2008b), derrubone (Hadden et al 2007), or kongensin A (Li et al 2016) have been studied. Most of them rely on blocking key interactions between Hsp90 and Cdc37 (Li et al 2018). On the other hand, the derrubone inhibitory mechanism seems to rely on the detrimental stabilization of a Hsp90: Cdc37:kinase complex (Hadden et al 2007).…”

Stress proteins: the biological functions in virus infection, present and challenges for target-based antiviral drug development

“…Notably, six active compounds have been identified after screening the NCGC compound library. 669 These compounds possess similar structural cores and have no effect on Hsp70 expression.…”