title: Benzimidazole inhibitors induce a DFG-out conformation of never in mitosis gene A-related kinase 2 (Nek2) without binding to the back pocket and reveal a nonlinear structure-activity relationship.
abstract: We describe herein the structure-activity relationship (SAR) and cocrystal structures of a series of Nek2 inhibitors derived from the published polo-like kinase 1 (Plk1) inhibitor (R)-1. Our studies reveal a nonlinear SAR for Nek2 and our cocrystal structures show that compounds in this series bind to a DFG-out conformation of Nek2 without extending into the enlarged back pocket commonly found in this conformation. These observations were further investigated, and structure-based design led to Nek2 inhibitors derived from (R)-1 with more than a hundred-fold selectivity against Plk1.
authors.affiliation: The Institute of Cancer Research, Cancer Research UK Cancer Therapeutics Unit, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom.
authors.forename: Savade
authors.initials: S
authors.lastname: Solanki
authors.forename: Paolo
authors.initials: P
authors.lastname: Innocenti
authors.forename: Corine
authors.initials: C
authors.lastname: Mas-Droux
authors.forename: Kathy
authors.initials: K
authors.lastname: Boxall
authors.forename: Caterina
authors.initials: C
authors.lastname: Barillari
authors.forename: Rob L M
authors.initials: RL
authors.lastname: van Montfort
authors.forename: G Wynne
authors.initials: GW
authors.lastname: Aherne
authors.forename: Richard
authors.initials: R
authors.lastname: Bayliss
authors.forename: Swen
authors.initials: S
authors.lastname: Hoelder
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D000072379:NIMA-Related Kinases; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C558736:4-(5-(1-methylpiperidin-4-yloxy)-1H-benzo(d)imidazol-1-yl)-2-(1-(2-(trifluoromethyl)phenyl)ethoxy)benzamide; D001549:Benzamides; D001562:Benzimidazoles; C089441:NEK2 protein, human; D000072379:NIMA-Related Kinases; D017346:Protein Serine-Threonine Kinases