Design and Optimization of Selective Protein Kinase C θ (PKCθ) Inhibitors for the Treatment of Autoimmune Diseases

• Published in: Journal of medicinal chemistry Vol. 56; no. 5; pp. 1799 - 1810
• Main Authors: Jimenez, Juan-Miguel, Boyall, Dean, Brenchley, Guy, Collier, Philip N, Davis, Christopher J, Fraysse, Damien, Keily, Shazia B, Henderson, Jaclyn, Miller, Andrew, Pierard, Francoise, Settimo, Luca, Twin, Heather C, Bolton, Claire M, Curnock, Adam P, Chiu, Peter, Tanner, Adam J, Young, Stephen
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.03.2013; Amer Chemical Soc
• Subjects: Animals; Autoimmune Diseases - drug therapy; Chemistry, Medicinal; Drug Design; Humans; Inhibitory Concentration 50; Interleukin-2 - antagonists & inhibitors; Isoenzymes - antagonists & inhibitors; Life Sciences & Biomedicine; Lymphocyte Activation - drug effects; Mice; Pharmacology & Pharmacy; Piperazines - chemical synthesis; Piperazines - pharmacokinetics; Protein Kinase C - antagonists & inhibitors; Protein Kinase C-theta; Protein Kinase Inhibitors - chemical synthesis; Pyridines - chemical synthesis; Pyridines - pharmacokinetics; Science & Technology; T-Lymphocytes - immunology; EFFECTOR; KAPPA-B ACTIVATION; T-CELL SURVIVAL; PHOSPHORYLATION; DEFICIENT; MICE; PROLIFERATION; COSTIMULATION; ABSENCE; SOTRASTAURIN
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm301465a

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).