Inhibition of the Human Hsc70 System by Small Ligands as a Potential Anticancer Approach

Abstract

Heat shock protein (Hsp) synthesis is upregulated in a wide range of cancers to provide the appropriate environment for tumor progression. The Hsp110 and Hsp70 families have been associated to cancer cell survival and resistance to chemotherapy. In this study, we explore the strategy of drug repurposing to find new Hsp70 and Hsp110 inhibitors that display toxicity against melanoma cancer cells. We found that the hits discovered using Apg2, a human representative of the Hsp110 family, as the initial target bind also to structural regions present in members of the Hsp70 family, and therefore inhibit the remodeling activity of the Hsp70 system. One of these compounds, the spasmolytic agent pinaverium bromide used for functional gastrointestinal disorders, inhibits the intracellular chaperone activity of the Hsp70 system and elicits its cytotoxic activity specifically in two melanoma cell lines by activating apoptosis. Docking and molecular dynamics simulations indicate that this compound interacts with regions located in the nucleotide-binding domain and the linker of the chaperones, modulating their ATPase activity. Thus, repurposing of pinaverium bromide for cancer treatment appears as a promising novel therapeutic approach.

Synthetic Small Molecule Modulators of Hsp70 and Hsp40 Chaperones as Promising Anticancer Agents

“…Thus, the repurposing of drugs appears promising and is not a one-way road. As far as drug repurposing is concerned, the disinfectant hexachlorophene ( 20 ) and the spasmolytic drug pinaverium bromide ( 4 ) are further interesting examples of Hsp70 inhibitory activity [ 50 , 82 ]. In contrast to the cationic mitochondria-targeting compounds with preference for mortalin binding, the anionic ruthenium complex 22 (KP1339) is an efficient Grp78 suppressor [ 85 , 86 , 87 , 88 ].…”

“…Compound 4 inhibited cell proliferation (IC 50 of ca. 10 µM) of A2058 melanoma cells and induced apoptosis in these cells [ 50 ]. Its binding site was located at the NBD and linker domains of Hsc70.…”

Irradiation induces DJ-1 secretion from esophageal squamous cell carcinoma cells to accelerate metastasis of bystander cells via a TGF-β1 positive feedback loop

“…A 70 kDa heat-shock cognate protein (HSC70/HSPA8) is a molecular chaperone that plays an essential role in cell survival [35,36]. HSC70 is a member of the heat-shock protein 70 family of proteins involved in protein folding, translocation or sorting, and regulation of signaling in cells [37]. It has been reported that the complex of HSC70 and MSG1 promotes Smad3-mediated transcription by enhancing coactivators [38].…”

A first-in-class inhibitor of Hsp110 molecular chaperones of pathogenic fungi

“…However, no inhibitors have been reported for any fungal Hsp110s. In fact, it has been challenging to develop modulators for Hsp110s in general due to a limited understanding of the molecular mechanisms of their chaperone activity, although inhibiting Hsp110s has been established as a potentially effective strategy against cancers 26 – 28 . To date, only one specific small molecule inhibitor has been reported for Hsp110s 29 , and this inhibitor is a competitor of ATP for a human Hsp110, which raises questions regarding specificity.…”