Isolation of a novel Thioflavin S-derived compound that inhibits BAG-1-mediated protein interactions and targets BRAF inhibitor-resistant cell lines

Enthammer, Marion, Papadakis, Emmanouil S., Gachet, Maria Salome, Deutsch, Martin, Schwaiger, Stefan, Koziel, Katarzyna, Ashraf, Muhammad I., Khalid, Sana, Wolber, Gerhard, Packham, Graham, Cutress, Ramsey I., Stuppner, Hermann and Troppmair, Jakob (2013) Isolation of a novel Thioflavin S-derived compound that inhibits BAG-1-mediated protein interactions and targets BRAF inhibitor-resistant cell lines. Molecular Cancer Therapeutics. (doi:10.1158/1535-7163.MCT-13-0142). (PMID:24048738)

Abstract

Protein-protein interactions mediated through the C-terminal BAG domain of BAG-1 are critical for cell survival and proliferation. Thioflavin S (NSC71948) - a mixture of compounds resulting from the methylation and sulfonation of primulin base - has been shown to dose-dependently inhibit the interaction between BAG-1 and Hsc70 in vitro. In human breast cancer cell lines, with high BAG-1 expression levels, Thioflavin S reduces the binding of BAG-1 to Hsc70, Hsp70 or CRAF and decreases proliferation and viability. Here we report the development of a protocol for the purification and isolation of biologically active constituents of Thioflavin S and the characterization of the novel compound Thio-2. Thio-2 blocked the growth of several transformed cell lines but had much weaker effects on untransformed cells. Thio-2 also inhibited the proliferation of melanoma cell lines that had become resistant to treatment with PLX4032, an inhibitor of mutant BRAF. In transformed cells Thio-2 interfered with intracellular signaling at the level of RAF but had no effect on the activation of AKT. Thio-2 decreased binding of BAG-1 to Hsc70 and to a lesser extent BRAF in vitro and in vivo, suggesting a possible mechanism of action. Given that tumors frequently develop resistance to kinase inhibitors during treatment, Thio-2 and related compounds may offer promising alternative strategies to currently available therapies.

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Contributors

Author: Graham Packham

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