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

  • Bioorg Med Chem Lett. 2013 May 15;23(10):3039-43. doi: 10.1016/j.bmcl.2013.03.013.
Longqin Hu  1 ,  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 ,  Benito Munoz
Affiliations
  • 1. Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA. [email protected]
PMID: 23562243 DOI: 10.1016/j.bmcl.2013.03.013
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 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.

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