Benzenesulphonamide inhibitors of the cytolytic protein perforin

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:27

Article

Spicer, Julie A.^1,2  Miller, Christian K.^1,2  O'Connor, Patrick D.^1,2  Jose, Jiney^1,2  Huttunen, Kristiina M.^1,3  Jaiswal, Jagdish K.^1,2  Denny, William A.^1,2  Akhlaghi, Hedieh⁴  Browne, Kylie A.⁴  Trapani, Joseph A.^4,5 

[1] Univ Auckland, Auckland Canc Soc, Fac Med & Hlth Sci, Res Ctr, Private Bag 92019, Auckland 1142, New Zealand

[2] Maurice Wilkins Ctr Mol Biodiscovery, Auckland, New Zealand

[3] Univ Eastern Finland, Sch Pharm, Fac Hlth Sci, POB 1627, FI-70211 Kuopio, Finland

[4] Peter MacCallum Canc Ctr, Canc Immunol Program, 305 Grattan St, Melbourne, Vic 3000, Australia

[5] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3052, Australia

关键词: Perforin;    Perforin inhibitor;    Benzenesulphonamide;    Bioisostere;    Immunosuppressant;   

DOI  :  10.1016/j.bmcl.2016.12.057

来源: Elsevier

【 摘 要 】

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. (C) 2017 The Authors. Published by Elsevier Ltd.

【 授权许可】

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