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

Bioorg Med Chem Lett
Authors
Keywords
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.

Year of Publication
2013
Journal
Bioorg Med Chem Lett
Volume
23
Issue
10
Pages
3039-43
Date Published
2013 May 15
ISSN
1464-3405
DOI
10.1016/j.bmcl.2013.03.013
PubMed ID
23562243
PubMed Central ID
PMC3648997
Links
Grant list
CA133791 / CA / NCI NIH HHS / United States
1 U54 HG005032- 1 / HG / NHGRI NIH HHS / United States
U54 HG005032 / HG / NHGRI NIH HHS / United States
MH093197 / MH / NIMH NIH HHS / United States
R03 MH093197 / MH / NIMH NIH HHS / United States
R01 CA133791 / CA / NCI NIH HHS / United States