Abstract
The protein kinase C (PKC) family of serine/threonine kinases is implicated in a wide variety of cellular processes. The PKC theta (PKCtheta) isoform is involved in TCR signal transduction and T cell activation and regulates T cell mediated diseases, including lung inflammation and airway hyperresponsiveness. Thus inhibition of PKCtheta enzyme activity by a small molecule represents an attractive strategy for the treatment of asthma. A PKCtheta high-throughput screening (HTS) campaign led to the identification of 4-(3-bromophenylamino)-5-(3,4-dimethoxyphenyl)-3-pyridinecarbonitrile 4a, a low microM ATP competitive PKCtheta inhibitor. Structure based hit-to-lead optimization led to the identification of 5-(3,4-dimethoxyphenyl)-4-(1H-indol-5-ylamino)-3-pyridinecarbonitrile 4p, a 70 nM PKCtheta inhibitor. Compound 4p was selective for inhibition of novel PKC isoforms over a panel of 21 serine/threonine, tyrosine, and phosphoinositol kinases, in addition to the conventional and atypical PKCs, PKCbeta, and PKCzeta, respectively. Compound 4p also inhibited IL-2 production in antiCD3/anti-CD28 activated T cells enriched from splenocytes.
MeSH terms
-
Animals
-
Crystallography, X-Ray
-
Dose-Response Relationship, Drug
-
Drug Evaluation, Preclinical
-
Female
-
Indoles / chemical synthesis
-
Indoles / chemistry
-
Indoles / pharmacology*
-
Interleukin-2 / antagonists & inhibitors
-
Interleukin-2 / biosynthesis
-
Isoenzymes / antagonists & inhibitors*
-
Isoenzymes / deficiency
-
Isoenzymes / drug effects
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Models, Molecular
-
Molecular Structure
-
Nitriles / chemical synthesis
-
Nitriles / chemistry
-
Nitriles / pharmacology*
-
Protein Kinase C / antagonists & inhibitors*
-
Protein Kinase C / deficiency
-
Protein Kinase C / drug effects
-
Protein Kinase C-theta
-
Protein Kinase Inhibitors / chemical synthesis
-
Protein Kinase Inhibitors / chemistry
-
Protein Kinase Inhibitors / pharmacology*
-
Pyridines / chemical synthesis
-
Pyridines / chemistry
-
Pyridines / pharmacology*
-
Spleen / cytology
-
Spleen / drug effects
-
Spleen / immunology
-
Stereoisomerism
-
Structure-Activity Relationship
-
T-Lymphocytes / drug effects
-
T-Lymphocytes / immunology
Substances
-
Indoles
-
Interleukin-2
-
Isoenzymes
-
Nitriles
-
Protein Kinase Inhibitors
-
Pyridines
-
Prkcq protein, mouse
-
Protein Kinase C
-
Protein Kinase C-theta