Suppression of CD4+ T cell activation by a novel inhibitor of Src family kinases.
The Src family kinases Lck and Fyn play an important role in T cell development and function. We have synthesized a novel small molecule, A-420983, which inhibits Lck and Fyn, as well as other Src family kinases, but has selectivity with respect to non-Src family kinases. A-420983 completely inhibited antigen-stimulated production of IFN-gamma and IL-4 by mouse Th1 and Th2 cells, respectively. Antigen-induced T cell proliferation was also blocked by treatment with A-420983. In contrast, IL-15-induced proliferation was unaffected by A-420983, suggesting that TCR-independent pathways of T cell activation were not impaired. When mice were dosed orally, A-420983 inhibited TCR-mediated c-jun and ZAP-70 phosphorylation in CD4+ T cells and suppressed the disease course of established EAE. Treatment with A-420983 for 7 days resulted in a block in thymocyte development at the CD4- CD8- stage, consistent with inhibition of Lck and Fyn in vivo. These results demonstrate that a small molecule inhibitor of Lck and Fyn can block TCR-induced T cell activation in vitro and in vivo. Furthermore, CNS demyelination mediated by activated encephalitogenic CD4+ T cells is dependent upon the kinase activity of these Src family members. We conclude that inhibition of Src family kinases may represent a promising strategy for the treatment of T cell-mediated disorders.
McRae
Bradford L
BL
Department of Pharmacology, Abbott Bioresearch Center, 100 Research Drive, Worcester, MA 01605-4314, USA. bradford.mcrae@abbott.com
Wallace
Craig
C
Dixon
Kathleen Fitzgerald
KF
Roux
Alyson
A
Mohan
Sukumari
S
Jia
Yong
Y
Presky
David H
DH
Tracey
Daniel E
DE
Hirst
Gavin C
GC
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008815:Mice, Inbred Strains; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
D011720:Pyrazoles; D011743:Pyrimidines; C014175:pyrazolo(3,4-d)pyrimidine; D019061:src-Family Kinases