title: Identification of new inhibitors of protein kinase R guided by statistical modeling.
abstract: We report the identification of new, structurally diverse inhibitors of interferon-induced, double-stranded RNA-activated protein kinase (PKR) using a combined experimental and computational approach. A training set with which to build a predictive statistical model was generated by screening a set of 80 known Ser/Thr kinase inhibitors against recombinant human PKR, resulting in the identification of 28 compounds from 18 chemical classes with <0.1 μM ≤ IC(50) ≤ 20 μM. The model built with this data was used to screen a database of 5 million commercially available compounds in silico to identify candidate inhibitors. Testing of 128 structurally diverse candidates resulted in the confirmation of 20 new inhibitors from 11 chemical classes with 2 μM ≤ IC(50) ≤ 20 μM. Testing of 34 analogs in the newly identified pyrimidin-2-amine active series provided initial SAR. One newly identified inhibitor, N-[2-(1H-indol-3-yl)ethyl]-4-(2-methyl-1H-indol-3-yl)pyrimidin-2-amine (compound 51), inhibited intracellular PKR activation in a dose-dependent manner in primary mouse macrophages without evident toxicity at effective concentrations.
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Ruslana
authors.initials: R
authors.lastname: Bryk
authors.forename: Kangyun
authors.initials: K
authors.lastname: Wu
authors.forename: Brian C
authors.initials: BC
authors.lastname: Raimundo
authors.forename: Paul E
authors.initials: PE
authors.lastname: Boardman
authors.forename: Ping
authors.initials: P
authors.lastname: Chao
authors.forename: Graeme L
authors.initials: GL
authors.lastname: Conn
authors.forename: Eric
authors.initials: E
authors.lastname: Anderson
authors.forename: James L
authors.initials: JL
authors.lastname: Cole
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Duffy
authors.forename: Carl
authors.initials: C
authors.lastname: Nathan
authors.forename: John H
authors.initials: JH
authors.lastname: Griffin
mesh_terms: D000818:Animals; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D015233:Models, Statistical; D015394:Molecular Structure; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D019892:eIF-2 Kinase