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

被引：229

作者：

Davies, Thomas G. ^{[1
]}

Wixted, William E. ^{[2
]}

Coyle, Joseph E. ^{[1
]}

Griffiths-Jones, Charlotte ^{[1
]}

Hearn, Keisha ^{[1
]}

McMenamin, Rachel ^{[1
]}

Norton, David ^{[1
]}

Rich, Sharna J. ^{[1
]}

Richardson, Caroline ^{[1
]}

Saxty, Gordon ^{[1
]}

Willems, Henriette M. G. ^{[1
]}

Woolford, Alison J. -A. ^{[1
]}

Cottom, Joshua E. ^{[3
]}

Kou, Jen-Pyng ^{[2
]}

Yonchuk, John G. ^{[2
]}

Feldser, Heidi G. ^{[2
]}

Sanchez, Yolanda ^{[2
]}

Foley, Joseph P. ^{[2
]}

Bolognese, Brian J. ^{[2
]}

Logan, Gregory ^{[2
]}

Podolin, Patricia L. ^{[2
]}

Yan, Hongxing ^{[2
]}

Callahan, James F. ^{[2
]}

Heightman, Tom D. ^{[1
]}

Kerns, Jeffrey K. ^{[2
]}

机构：

[1] Astex Pharmaceut, 436 Cambridge Sci Pk, Cambridge CB4 0QA, England

[2] GlaxoSmithKline, 709 Swedeland Rd, King Of Prussia, PA 19406 USA

[3] GlaxoSmithKline, 1250 South Collegeville Rd, Collegeville, PA 19426 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 08期

关键词：

SMOKE-INDUCED EMPHYSEMA; STRUCTURAL BASIS; DLG MOTIFS; NRF2; INDUCTION; BINDING; LIGASE; STRESS; UBIQUITINATION; ELECTROPHILE;

D O I：

10.1021/acs.jmedchem.6b00228

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：3991 / 4006

页数：16

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