title: Design and optimization of selective protein kinase C θ (PKCθ) inhibitors for the treatment of autoimmune diseases.
abstract: Protein kinase C θ (PKCθ) has a central role in T cell activation and survival; however, the dependency of T cell responses to the inhibition of this enzyme appears to be dictated by the nature of the antigen and by the inflammatory environment. Studies in PKCθ-deficient mice have demonstrated that while antiviral responses are PKCθ-independent, T cell responses associated with autoimmune diseases are PKCθ-dependent. Thus, potent and selective inhibition of PKCθ is expected to block autoimmune T cell responses without compromising antiviral immunity. Herein, we describe the development of potent and selective PKCθ inhibitors, which show exceptional potency in cells and in vivo. By use of a structure based rational design approach, a 1000-fold improvement in potency and 76-fold improvement in selectivity over closely related PKC isoforms such as PKCδ were obtained from the initial HTS hit, together with a big improvement in lipophilic efficiency (LiPE).
authors: Department of Chemistry, Vertex Pharmaceuticals (Europe) Ltd., 88 Milton Park, Abingdon, Oxfordshire OX14 4RY, UK. juan-miguel_jimenez@vrtx.com
authors: Juan-Miguel
authors: JM
authors: Jimenez
authors: Dean
authors: D
authors: Boyall
authors: Guy
authors: G
authors: Brenchley
authors: Philip N
authors: PN
authors: Collier
authors: Christopher J
authors: CJ
authors: Davis
authors: Damien
authors: D
authors: Fraysse
authors: Shazia B
authors: SB
authors: Keily
authors: Jaclyn
authors: J
authors: Henderson
authors: Andrew
authors: A
authors: Miller
authors: Francoise
authors: F
authors: Pierard
authors: Luca
authors: L
authors: Settimo
authors: Heather C
authors: HC
authors: Twin
authors: Claire M
authors: CM
authors: Bolton
authors: Adam P
authors: AP
authors: Curnock
authors: Peter
authors: P
authors: Chiu
authors: Adam J
authors: AJ
authors: Tanner
authors: Stephen
authors: S
authors: Young
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy*; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D007376:Interleukin-2 / Q000037:antagonists & inhibitors; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D000074121:Protein Kinase C-theta; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis*; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: C580999:2-(4-(3-chloro-5-fluoro-6-(1H-pyrazolo(3,4-b)pyridin-3-yl)pyridin-2-yl)piperazin-2-yl)-3-methylbutan-2-ol; D007376:Interleukin-2; D007527:Isoenzymes; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta