Discovery of a small-molecule inhibitor and cellular probe of Keap1-Nrf2 protein-protein interaction

作者：Hu Longqin^*; Magesh Sadagopan; Chen Lin; Wang Lili; Lewis Timothy A; Chen Yu; Khodier Carol; Inoyama Daigo; Beamer Lesa J; Emge Thomas J; Shen Jian; Kerrigan John E; Ah Ng Tony Kong; Dandapani Sivaraman; Palmer Michelle; Schreiber Stuart L; Munoz Benito

来源：Bioorganic & Medicinal Chemistry Letters, 2013, 23(10): 3039-3043.

DOI：10.1016/j.bmcl.2013.03.013

• Keap1
• Nrf2
• Inhibitors of protein-protein interaction
• Nrf2 activation

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 100x 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 bindin

• 出版日期2013-5-15