Diarylthiophenes as inhibitors of the pore-forming protein perforin

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:26

Article

Miller, Christian K.^1,2  Huttunen, Kristiina M.^1,3  Denny, William A.^1,2  Jaiswal, Jagdish K.¹  Ciccone, Annette⁴  Browne, Kylie A.⁴  Trapani, Joseph A.^4,5  Spicer, Julie A.^1,2 

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

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

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

[4] Peter MacCallum Canc Ctr, Canc Immunol Program, Melbourne, Vic 3002, Australia

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

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

DOI  :  10.1016/j.bmcl.2015.12.003

来源: Elsevier

【 摘 要 】

Evolution from a furan-containing high-throughput screen (HTS) hit (1) resulted in isobenzofuran-1(3H)-one (2) as a potent inhibitor of the function of both isolated perforin protein and perforin delivered in situ by intact KHYG-1 NK cells. In the current study, structure-activity relationship (SAR) development towards a novel series of diarylthiophene analogues has continued through the use of substituted-benzene and -pyridyl moieties as bioisosteres for 2-thioxoimidazolidin-4-one (A) on a thiophene (B) -isobenzofuranone (C) scaffold. The resulting compounds were tested for their ability to inhibit perforin lytic activity in vitro. Carboxamide (23) shows a 4-fold increase over (2) in lytic activity against isolated perforin and provides good rationale for continued development within this class. (C) 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license.

【 授权许可】

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