2. Academic Validation
  3. 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

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

  • J Med Chem. 2016 Apr 28;59(8):3991-4006. doi: 10.1021/acs.jmedchem.6b00228.
Thomas G Davies 1,  William E Wixted 2,  Joseph E Coyle 1,  Charlotte Griffiths-Jones 1,  Keisha Hearn 1,  Rachel McMenamin 1,  David Norton 1,  Sharna J Rich 1,  Caroline Richardson 1,  Gordon Saxty 1,  Henriëtte M G Willems 1,  Alison J-A Woolford 1,  Joshua E Cottom 3,  Jen-Pyng Kou 2,  John G Yonchuk 2,  Heidi G Feldser 2,  Yolanda Sanchez 2,  Joseph P Foley 2,  Brian J Bolognese 2,  Gregory Logan 2,  Patricia L Podolin 2,  Hongxing Yan 2,  James F Callahan 2,  Tom D Heightman 1,  Jeffrey K Kerns 2
Affiliations

Affiliations

  • 1 Astex Pharmaceuticals, 436 Cambridge Science Park, Cambridge CB4 0QA, U.K.
  • 2 GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
  • 3 GlaxoSmithKline Pharmaceuticals, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
PMID: 27031670 DOI: 10.1021/acs.jmedchem.6b00228
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.

Figures
Products