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Issue 1, 2016
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Par-4 secretion: stoichiometry of 3-arylquinoline binding to vimentin

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Advanced prostate tumors usually metastasize to the lung, bone, and other vital tissues and are resistant to conventional therapy. Prostate apoptosis response-4 protein (Par-4) is a tumor suppressor that causes apoptosis in therapy-resistant prostate cancer cells by binding specifically to a receptor, Glucose-regulated protein-78 (GRP78), found only on the surface of cancer cells. 3-Arylquinolines or “arylquins” induce normal cells to release Par-4 from the intermediate filament protein, vimentin and promote Par-4 secretion that targets cancer cells in a paracrine manner. A structure–activity study identified arylquins that promote Par-4 secretion, and an evaluation of arylquin binding to the hERG potassium ion channel using a [3H]-dofetilide binding assay permitted the identification of structural features that separated this undesired activity from the desired Par-4 secretory activity. A binding study that relied on the natural fluorescence of arylquins and that used the purified rod domain of vimentin (residues 99-411) suggested that the mechanism behind Par-4 release involved arylquin binding to multiple sites in the rod domain.

Graphical abstract: Par-4 secretion: stoichiometry of 3-arylquinoline binding to vimentin

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Publication details

The article was received on 22 Sep 2015, accepted on 03 Nov 2015 and first published on 03 Nov 2015

Article type: Paper
DOI: 10.1039/C5OB01980J
Citation: Org. Biomol. Chem., 2016,14, 74-84
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    Par-4 secretion: stoichiometry of 3-arylquinoline binding to vimentin

    V. M. Sviripa, R. Burikhanov, J. M. Obiero, Y. Yuan, J. R. Nickell, L. P. Dwoskin, C. Zhan, C. Liu, O. V. Tsodikov, V. M. Rangnekar and D. S. Watt, Org. Biomol. Chem., 2016, 14, 74
    DOI: 10.1039/C5OB01980J

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