title: Discovery of selective and orally bioavailable protein kinase Cθ (PKCθ) inhibitors from a fragment hit.
abstract: Protein kinase Cθ (PKCθ) regulates a key step in the activation of T cells. On the basis of its mechanism of action, inhibition of this kinase is hypothesized to serve as an effective therapy for autoimmune diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis. Herein, the discovery of a small molecule PKCθ inhibitor is described, starting from a fragment hit 1 and advancing to compound 41 through the use of structure-based drug design. Compound 41 demonstrates excellent in vitro activity, good oral pharmacokinetics, and efficacy in both an acute in vivo mechanistic model and a chronic in vivo disease model but suffers from tolerability issues upon chronic dosing.
authors.affiliation: AbbVie Bioresearch Center , 381 Plantation Street, Worcester, Massachusetts 01605, United States.
authors.forename: Dawn M
authors.initials: DM
authors.lastname: George
authors.forename: Eric C
authors.initials: EC
authors.lastname: Breinlinger
authors.forename: Michael
authors.initials: M
authors.lastname: Friedman
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jianfei
authors.initials: J
authors.lastname: Wang
authors.forename: Maria
authors.initials: M
authors.lastname: Argiriadi
authors.forename: Pratima
authors.initials: P
authors.lastname: Bansal-Pakala
authors.forename: Martine
authors.initials: M
authors.lastname: Barth
authors.forename: David B
authors.initials: DB
authors.lastname: Duignan
authors.forename: Prisca
authors.initials: P
authors.lastname: Honore
authors.forename: QingYu
authors.initials: Q
authors.lastname: Lang
authors.forename: Scott
authors.initials: S
authors.lastname: Mittelstadt
authors.forename: Dominique
authors.initials: D
authors.lastname: Potin
authors.forename: Lian
authors.initials: L
authors.lastname: Rundell
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Edmunds
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001169:Arthritis, Experimental / Q000188:drug therapy; D001682:Biological Availability; D002478:Cells, Cultured; D002853:Chromatography, Liquid; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D055808:Drug Discovery; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D013058:Mass Spectrometry; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D000074121:Protein Kinase C-theta; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D051381:Rats; D054852:Small Molecule Libraries / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects
chemical_list: D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta