ABSTRACT
PF-956980 is a selective inhibitor of JAK3, related in structure to CP-690550, a compound being evaluated in clinical trials for rheumatoid arthritis and prevention of allograft rejection. PF-956980 has been evaluated against a panel of 30 kinases, and found to have nanomolar potency against only JAK3. Cellular and whole blood activity of this compound parallels its potency and selectivity in enzyme assays. It was effective in vivo at inhibiting the delayed type hypersensivity reaction in mice. We compared 2 commercially available JAK3 inhibitors (WHI-P131 and WHI-P154) in the same panel of biochemical and cellular assays and found them to be neither potent nor selective for JAK3. Both were found to be nanomolar inhibitors of the EGF receptor family of kinases. As these compounds have been used in numerous publications in the transplant and autoimmune disease literature, their specificity should be considered when interpreting these results.
Subject(s)
Enzyme Inhibitors/pharmacology , Janus Kinase 3/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/pharmacology , Pyrroles/pharmacology , Arthritis, Rheumatoid/drug therapy , Clinical Trials as Topic , Enzyme Inhibitors/therapeutic use , Graft Rejection/prevention & control , Humans , Kinetics , Pyrimidines/therapeutic use , Pyrroles/therapeutic use , Quinazolines/pharmacology , Quinazolines/therapeutic useABSTRACT
A cell-based assay for the chemokine G-protein-coupled receptor CCR4 was developed, and used to screen a small-molecule compound collection in a multiplex format. A series of bipiperidinyl carboxylic acid amides amenable to parallel chemistry were derived that were potent and selective antagonists of CCR4. One prototype compound was shown to be active in a functional model of chemotaxis, making it a useful chemical tool to explore the role of CCR4 in asthma, allergy, diabetes, and cancer.