title: Binding mode and structure-activity relationships around direct inhibitors of the Nrf2-Keap1 complex.
abstract: An X-ray crystal structure of Kelch-like ECH-associated protein (Keap1) co-crystallised with (1S,2R)-2-[(1S)-1-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-2-carbonyl]cyclohexane-1-carboxylic acid (compound (S,R,S)-1 a) was obtained. This X-ray crystal structure provides breakthrough experimental evidence for the true binding mode of the hit compound (S,R,S)-1 a, as the ligand orientation was found to differ from that of the initial docking model, which was available at the start of the project. Crystallographic elucidation of this binding mode helped to focus and drive the drug design process more effectively and efficiently.
authors: UCB Pharma, UCB NewMedicines, Chemin du Foriest, 1420 Braine-l'Alleud (Belgium). eric.jnoff@ucb.com.
authors: Eric
authors: E
authors: Jnoff
authors: Claudia
authors: C
authors: Albrecht
authors: John J
authors: JJ
authors: Barker
authors: Oliver
authors: O
authors: Barker
authors: Edward
authors: E
authors: Beaumont
authors: Steven
authors: S
authors: Bromidge
authors: Frederick
authors: F
authors: Brookfield
authors: Mark
authors: M
authors: Brooks
authors: Christian
authors: C
authors: Bubert
authors: Tom
authors: T
authors: Ceska
authors: Vincent
authors: V
authors: Corden
authors: Graham
authors: G
authors: Dawson
authors: Stephanie
authors: S
authors: Duclos
authors: Tara
authors: T
authors: Fryatt
authors: Christophe
authors: C
authors: Genicot
authors: Emilie
authors: E
authors: Jigorel
authors: Jason
authors: J
authors: Kwong
authors: Rosemary
authors: R
authors: Maghames
authors: Innocent
authors: I
authors: Mushi
authors: Richard
authors: R
authors: Pike
authors: Zara A
authors: ZA
authors: Sands
authors: Myron A
authors: MA
authors: Smith
authors: Christopher C
authors: CC
authors: Stimson
authors: Jean-Philippe
authors: JP
authors: Courade
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors*; D000818:Animals; D018360:Crystallography, X-Ray; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors*; D010797:Phthalimides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000593535:2-(1-((1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-2-carbonyl)cyclohexane-1-carboxylic acid; D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines; C431364:KEAP1 protein, human; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; D010797:Phthalimides
keywords: CNS; Keap1; Nrf2; co-crystal structures; docking; structure-activity relationships