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Jak3 is a protein tyrosine kinase that is associated with the shared gamma chain of receptors for cytokines IL2, IL4, IL7, IL9, and IL13. We have discovered that a pyridone-containing tetracycle (6) may be prepared from trisubstituted imidazole (5) in high yield by irradiation with >350 nm light. Compound 6 inhibits Jak3 with K(I)=5 nM; it also inhibits Jak family members Tyk2 and Jak2 with IC(50)=1 nM and murine Jak1with IC(50)=15 nM. Compound 6 was tested as an inhibitor of 21 other protein kinases; it inhibited these kinases with IC(50)s ranging from 130 nM to >10 microM. Compound 6 also blocks IL2 and IL4 dependent proliferation of CTLL cells and inhibits the phosphorylation of STAT5 (an in vivo substrate of the Jak family) as measured by Western blotting.

Original publication

DOI

10.1016/s0960-894x(02)00106-3

Type

Journal article

Journal

Bioorganic & medicinal chemistry letters

Publication Date

04/2002

Volume

12

Pages

1219 - 1223

Addresses

Merck Research Laboratories, Merck & Co., 80M-127, PO Box 2000, Rahway, NJ 07065-0900, USA. jed_thompson@merck.com

Keywords

Animals, Mice, Pyridones, Milk Proteins, DNA-Binding Proteins, Trans-Activators, Interleukin-2, Interleukin-4, Enzyme Inhibitors, Cell Division, Phosphorylation, Photochemistry, STAT5 Transcription Factor, Protein-Tyrosine Kinases, Janus Kinase 3