کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
10595905 981877 2013 5 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Discovery of a small-molecule inhibitor and cellular probe of Keap1-Nrf2 protein-protein interaction
کلمات کلیدی
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
Discovery of a small-molecule inhibitor and cellular probe of Keap1-Nrf2 protein-protein interaction
چکیده انگلیسی
A high-throughput screen (HTS) of the MLPCN library using a homogenous fluorescence polarization assay identified a small molecule as a first-in-class direct inhibitor of Keap1-Nrf2 protein-protein interaction. The HTS hit has three chiral centers; a combination of flash and chiral chromatographic separation demonstrated that Keap1-binding activity resides predominantly in one stereoisomer (SRS)-5 designated as ML334 (LH601A), which is at least 100× more potent than the other stereoisomers. The stereochemistry of the four cis isomers was assigned using X-ray crystallography and confirmed using stereospecific synthesis. (SRS)-5 is functionally active in both an ARE gene reporter assay and an Nrf2 nuclear translocation assay. The stereospecific nature of binding between (SRS)-5 and Keap1 as well as the preliminary but tractable structure-activity relationships support its use as a lead for our ongoing optimization
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 23, Issue 10, 15 May 2013, Pages 3039-3043
نویسندگان
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