title: 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.
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Cambridge CB4 0QA, U.K.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Davies
authors.affiliation: GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: William E
authors.initials: WE
authors.lastname: Wixted
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Cambridge CB4 0QA, U.K.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Coyle
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Cambridge CB4 0QA, U.K.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Griffiths-Jones
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Cambridge CB4 0QA, U.K.
authors.forename: Keisha
authors.initials: K
authors.lastname: Hearn
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Cambridge CB4 0QA, U.K.
authors.forename: Rachel
authors.initials: R
authors.lastname: McMenamin
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Cambridge CB4 0QA, U.K.
authors.forename: David
authors.initials: D
authors.lastname: Norton
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Cambridge CB4 0QA, U.K.
authors.forename: Sharna J
authors.initials: SJ
authors.lastname: Rich
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Cambridge CB4 0QA, U.K.
authors.forename: Caroline
authors.initials: C
authors.lastname: Richardson
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Cambridge CB4 0QA, U.K.
authors.forename: Gordon
authors.initials: G
authors.lastname: Saxty
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Cambridge CB4 0QA, U.K.
authors.forename: Henriëtte M G
authors.initials: HM
authors.lastname: Willems
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Cambridge CB4 0QA, U.K.
authors.forename: Alison J-A
authors.initials: AJ
authors.lastname: Woolford
authors.affiliation: GlaxoSmithKline Pharmaceuticals, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Cottom
authors.affiliation: GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Jen-Pyng
authors.initials: JP
authors.lastname: Kou
authors.affiliation: GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: John G
authors.initials: JG
authors.lastname: Yonchuk
authors.affiliation: GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Heidi G
authors.initials: HG
authors.lastname: Feldser
authors.affiliation: GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Sanchez
authors.affiliation: GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Foley
authors.affiliation: GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bolognese
authors.affiliation: GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Gregory
authors.initials: G
authors.lastname: Logan
authors.affiliation: GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Podolin
authors.affiliation: GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Hongxing
authors.initials: H
authors.lastname: Yan
authors.affiliation: GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: James F
authors.initials: JF
authors.lastname: Callahan
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Cambridge CB4 0QA, U.K.
authors.forename: Tom D
authors.initials: TD
authors.lastname: Heightman
authors.affiliation: GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Kerns
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding
chemical_list: C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2