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
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- 作者：Thomas G. Davies ; William E. Wixted ; Joseph E. Coyle ; Charlotte Griffiths-Jones ; Keisha Hearn ; Rachel McMenamin ; David Norton ; Sharna J. Rich ; Caroline Richardson ; Gordon Saxty ; Henriëtte M. G. Willems ; Alison J.-A. Woolford ; Joshua E. Cottom ; Jen-Pyng Kou ; John G. Yonchuk ; Heidi G. Feldser ; Yolanda Sanchez ; Joseph P. Foley ; Brian J. Bolognese ; Gregory Logan ; Patricia L. Podolin ; Hongxing Yan ; James F. Callahan ; Tom D. Heightman ; Jeffrey K. Kerns
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：April 28, 2016
- 年：2016
- 卷：59
- 期：8
- 页码：3991-4006
- 全文大小：829K
- 年卷期：0
- ISSN：1520-4804
文摘
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.