Abstract
Heat shock protein 90 (Hsp90) is a significant target in the development of rational cancer therapy due to its role at the crossroads of multiple signaling pathways associated with cell proliferation and cell viability. The relevance of Hsp90 as a therapeutic target for numerous diseases states has prompted the identification and optimization of novel Hsp90 inhibitors as an emerging therapeutic strategy. We performed a screening aimed to identify novel Hsp90 inhibitors among several natural compounds and we focused on the iminosugar (+)-lentiginosine, a natural amyloglucosidases inhibitor, for its peculiar bioactivity profile. Characterization of Hsp90 inhibition was performed using a panel of chemical and biological approaches, including limited proteolysis, biochemical and cellular assays. Our result suggested that the middle domain of Hsp90, as opposed to its ATP-binding pocket, is a promising binding site for new classes of Hsp90 inhibitors with multi-target anti-cancer potential.
Highlights
Heat shock protein 90 (Hsp90) is an abundant molecular chaperone involved in a variety of cellular processes ranging from signal transduction to viral replication
Our results demonstrated that in vitro (+)-lentiginosine represent an innovative scaffold for the design of new Hsp90 inhibitors interacting with the protein middle domain
In order to evaluate the ability of iminosugars to affect the biological activity of Hsp90, we started a chemical-biological study using (+)-lentiginosine as model
Summary
Heat shock protein 90 (Hsp90) is an abundant molecular chaperone involved in a variety of cellular processes ranging from signal transduction to viral replication. Our results demonstrated that in vitro (+)-lentiginosine represent an innovative scaffold for the design of new Hsp90 inhibitors interacting with the protein middle domain.
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