Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10595905 | Bioorganic & Medicinal Chemistry Letters | 2013 | 5 Pages |
Abstract
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 100Ã 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
Keywords
Related Topics
Physical Sciences and Engineering
Chemistry
Organic Chemistry
Authors
Longqin Hu, Sadagopan Magesh, Lin Chen, Lili Wang, Timothy A. Lewis, Yu Chen, Carol Khodier, Daigo Inoyama, Lesa J. Beamer, Thomas J. Emge, Jian Shen, John E. Kerrigan, Ah-Ng Tony Kong, Sivaraman Dandapani, Michelle Palmer, Stuart L. Schreiber,