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Monoacidic Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1:NRF2) Protein-Protein Interaction with High Cell Potency Identified by Fragment-Based Discovery.

Abstract：

:KEAP1 is the key regulator of the NRF2-mediated cytoprotective response, and increasingly recognized as a target for diseases involving oxidative stress. Pharmacological intervention has focused on molecules that decrease NRF2-ubiquitination through covalent modification of KEAP1 cysteine residues, but such electrophilic compounds lack selectivity and may be associated with off-target toxicity. We report here the first use of a fragment-based approach to directly target the KEAP1 Kelch-NRF2 interaction. X-ray crystallographic screening identified three distinct "hot-spots" for fragment binding within the NRF2 binding pocket of KEAP1, allowing progression of a weak fragment hit to molecules with nanomolar affinity for KEAP1 while maintaining drug-like properties. This work resulted in a promising lead compound which exhibits tight and selective binding to KEAP1, and activates the NRF2 antioxidant response in cellular and in vivo models, thereby providing a high quality chemical probe to explore the therapeutic potential of disrupting the KEAP1-NRF2 interaction.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Davies TG,Wixted WE,Coyle JE,Griffiths-Jones C,Hearn K,McMenamin R,Norton D,Rich SJ,Richardson C,Saxty G,Willems HM,Woolford AJ,Cottom JE,Kou JP,Yonchuk JG,Feldser HG,Sanchez Y,Foley JP,Bolognese BJ,Logan G,Podoli

doi

10.1021/acs.jmedchem.6b00228

subject

Has Abstract

pub_date

2016-04-28 00:00:00

pages

3991-4006

issue

8

eissn

0022-2623

issn

1520-4804

journal_volume

59

pub_type

杂志文章

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