title: Combinatorial approach to identification of tyrphostin inhibitors of cytokine signaling.
abstract: Aberrant or deregulated activity of certain cellular kinases has been shown to cause certain malignancies and other disorders. The tyrphostin molecule AG490 inhibits the action of the janus kinases JAK2 and JAK3. JAK2 is an indispensable molecule for transducing the signals conveyed by a large number of cytokines including IL-3 while JAK3 is essential for signaling by a smaller number of cytokines including IL-7. A synthetic combinatorial chemical library containing 599 compounds was created and screened for the ability to inhibit proliferation of IL3- and IL7-dependent cell lines to focus on molecules that interrupt those signaling pathways. This screen identified a meta-trifluoromethyl derivative of AG490, 5H4, that is approximately twice as potent as AG490 in cell-based assays. 5H4 blocked the factor-dependent proliferation of both of these cell lines, actively promoted cell death, and diminished the JAK kinase activity. Administration of 5H4 to lymphoma-prone IL-7 transgenic mice reduced their spontaneous lymphadenopathy. The improved characteristics of this novel compound bring this class of molecules closer to therapeutic utility.
authors.affiliation: Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Gu
authors.forename: Hui
authors.initials: H
authors.lastname: Zhuang
authors.forename: Brian
authors.initials: B
authors.lastname: Safina
authors.forename: Xiao-yi
authors.initials: XY
authors.lastname: Xiao
authors.forename: Wallace W
authors.initials: WW
authors.lastname: Bradford
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Rich
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D020650:Combinatorial Chemistry Techniques; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D007377:Interleukin-3 / Q000378:metabolism*; D015851:Interleukin-7 / Q000235:genetics / Q000378:metabolism*; D053616:Janus Kinase 3; D008206:Lymphatic Diseases / Q000209:etiology / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D020032:Tyrphostins / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D007377:Interleukin-3; D015851:Interleukin-7; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D011505:Protein-Tyrosine Kinases; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3