Substituted arylsulphonamides as inhibitors of perforin-mediated lysis
AuthorSpicer, JA; Miller, CK; O'Connor, PD; Jose, J; Huttunen, KM; Jaiswal, JK; Denny, WA; Akhlaghi, H; Browne, KA; Trapani, JA
Source TitleEuropean Journal of Medicinal Chemistry
PublisherELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
University of Melbourne Author/sTrapani, Joseph
AffiliationSir Peter MacCallum Department of Oncology
Document TypeJournal Article
CitationsSpicer, 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). Substituted arylsulphonamides as inhibitors of perforin-mediated lysis. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 137, pp.139-155. https://doi.org/10.1016/j.ejmech.2017.05.048.
Access StatusOpen Access
The structure-activity relationships for a series of arylsulphonamide-based inhibitors of the pore-forming protein perforin have been explored. Perforin is a key component of the human immune response, however inappropriate activity has also been implicated in certain auto-immune and therapy-induced conditions such as allograft rejection and graft versus host disease. Since perforin is expressed exclusively by cells of the immune system, inhibition of this protein would be a highly selective strategy for the immunosuppressive treatment of these disorders. Compounds from this series were demonstrated to be potent inhibitors of the lytic action of both isolated recombinant perforin and perforin secreted by natural killer cells in vitro. Several potent and soluble examples were assessed for in vivo pharmacokinetic properties and found to be suitable for progression to an in vivo model of transplant rejection.
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