1432065-36-5Relevant academic research and scientific papers
Discovery of a small-molecule inhibitor and cellular probe of Keap1-Nrf2 protein-protein interaction
Hu, Longqin,Magesh, Sadagopan,Chen, Lin,Wang, Lili,Lewis, Timothy A.,Chen,Khodier, Carol,Inoyama, Daigo,Beamer, Lesa J.,Emge, Thomas J.,Shen, Jian,Kerrigan, John E.,Kong, Ah-Ng Tony,Dandapani, Sivaraman,Palmer, Michelle,Schreiber, Stuart L.,Munoz, Benito
, p. 3039 - 3043 (2013)
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.
