title: Structure-based optimization of PKCtheta inhibitors.
abstract: PKCtheta (protein kinase Ctheta) is a central signalling molecule in the T-cell receptor activation pathway and is a target for treatment of a number of diseases. Several PKC inhibitors are in the drug-discovery pharmaceutical programmes today for the treatment of cancer, diabetes and arthritis. CD4(+) T-lymphocytes also play a critical role in the initiation and progression of allergic airway inflammation. Our goal is the development of PKCtheta antagonists as a means to control asthma and autoimmune diseases, using the strategy based on developing small-molecule agents that would block the enzyme's catalytic activity. Here, we discuss our work on the discovery of lead chemical series and review our X-ray structural and modelling approaches, including a structure-surrogate strategy that helped guide us in the lead compound optimizations.
authors.affiliation: Chemical and Screening Sciences, Wyeth Research, Cambridge, MA 02140, U.S.A. lmosyak@wyeth.com
authors.forename: L
authors.initials: L
authors.lastname: Mosyak
authors.forename: Z
authors.initials: Z
authors.lastname: Xu
authors.forename: D
authors.initials: D
authors.lastname: Joseph-McCarthy
authors.forename: N
authors.initials: N
authors.lastname: Brooijmans
authors.forename: W
authors.initials: W
authors.lastname: Somers
authors.forename: D
authors.initials: D
authors.lastname: Chaudhary
mesh_terms: D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000074121:Protein Kinase C-theta; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013379:Substrate Specificity
chemical_list: D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta