Journal article

Exploration of a Series of 5-Arylidene-2-thioxoimidazolidin-4-ones as Inhibitors of the Cytolytic Protein Perforin

Julie A Spicer, Gersande Lena, Dani M Lyons, Kristiina M Huttunen, Christian K Miller, Patrick D O'Connor, Matthew Bull, Nuala Helsby, Stephen MF Jamieson, William A Denny, Annette Ciccone, Kylie A Browne, Jamie A Lopez, Jesse Rudd-Schmidt, Ilia Voskoboinik, Joseph A Trapani



A series of novel 5-arylidene-2-thioxoimidazolidin-4-ones were investigated as inhibitors of the lymphocyte-expressed pore-forming protein perforin. Structure-activity relationships were explored through variation of an isoindolinone or 3,4-dihydroisoquinolinone subunit on a fixed 2-thioxoimidazolidin-4-one/thiophene core. The ability of the resulting compounds to inhibit the lytic activity of both isolated perforin protein and perforin delivered in situ by natural killer cells was determined. A number of compounds showed excellent activity at concentrations that were nontoxic to the killer cells, and several were a significant improvement on previous classes of inhibitors, being substantial..

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Awarded by Wellcome Trust

Awarded by Academy of Finland

Funding Acknowledgements

This work was supported by the Wellcome Trust (Grant 092717) and the Auckland Division of the Cancer Society of New Zealand. K.M.H. thanks the Academy of Finland (Grant 135439) and the Finnish Cultural Foundation for financial support. J.A.L. is supported by an National Health & Medical Research Council (NH&MRC) Postdoctoral Training Fellowship, and I.V. is supported by a fellowship and grants from the NH&MRC. We also thank Rod Nyland for the synthesis of compounds 52 and 53, Sisira Kumara and Karin Tan for HPLC studies, and Maruta Boyd and Shannon Black for NMR studies.