Benzenesulphonamide inhibitors of the cytolytic protein perforin
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2017-02-01
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Bioorganic and Medicinal Chemistry Letters
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PERGAMON-ELSEVIER SCIENCE LTD
Melbourne Authors
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Sir Peter MacCallum Department of Oncology
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Journal Article
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Spicer, J. A., Miller, C. K., O'Connor, P. D., Jose, J., Huttunen, K. M., Jaiswal, J. K., Denny, W. A., Akhlaghi, H., Browne, K. A. & Trapani, J. A. (2017). Benzenesulphonamide inhibitors of the cytolytic protein perforin. Bioorganic and Medicinal Chemistry Letters, 27 (4), pp.1050-1054. https://doi.org/10.1016/j.bmcl.2016.12.057.
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Abstract
The pore-forming protein perforin is a key component of mammalian cell-mediated immunity and essential to the pathway that allows elimination of virus-infected and transformed cells. Perforin activity has also been implicated in certain auto-immune conditions and therapy-induced conditions such as allograft rejection and graft versus host disease. An inhibitor of perforin activity could be used as a highly specific immunosuppressive treatment for these conditions, with reduced side-effects compared to currently accepted therapies. Previously identified first-in-class inhibitors based on a 2-thioxoimidazolidin-4-one core show suboptimal physicochemical properties and toxicity toward the natural killer (NK) cells that secrete perforin in vivo. The current benzenesulphonamide-based series delivers a non-toxic bioisosteric replacement possessing improved solubility.