Selective Itk inhibitors block T-cell activation and murine lung inflammation.
Nonreceptor protein tyrosine kinases including Lck, ZAP-70, and Itk play essential roles in T-cell receptor (TCR) signaling. Gene knockout studies have revealed that mice lacking these individual kinases exhibit various degrees of immunodeficiency; however, highly selective small molecule inhibitors of these kinases as potential immunosuppressive agents have not been identified. Here we discovered two novel compounds, BMS-488516 and BMS-509744, that potently and selectively inhibit Itk kinase activity. The compounds reduce TCR-induced functions including PLCgamma1 tyrosine phosphorylation, calcium mobilization, IL-2 secretion, and T-cell proliferation in vitro in both human and mouse cells. The inhibitors suppress the production of IL-2 induced by anti-TCR antibody administered to mice. BMS-509744 also significantly diminishes lung inflammation in a mouse model of ovalbumin-induced allergy/asthma. Our findings represent the first description of selective inhibitors to probe human Itk function and its associated pathway, and support the hypothesis that Itk is a therapeutic target for immunosuppressive and inflammatory diseases.
Lin
Tai-An
TA
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA. taian.lin@bms.com
McIntyre
Kim W
KW
Das
Jagabandhu
J
Liu
Chunjian
C
O'Day
Kathleen D
KD
Penhallow
Becky
B
Hung
Chen-Yi
CY
Whitney
Gena S
GS
Shuster
David J
DJ
Yang
XiaoXia
X
Townsend
Robert
R
Postelnek
Jennifer
J
Spergel
Steven H
SH
Lin
James
J
Moquin
Robert V
RV
Furch
Joseph A
JA
Kamath
Amrita V
AV
Zhang
Hongjian
H
Marathe
Punit H
PH
Perez-Villar
Juan J
JJ
Doweyko
Arthur
A
Killar
Loran
L
Dodd
John H
JH
Barrish
Joel C
JC
Wityak
John
J
Kanner
Steven B
SB
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019169:Jurkat Cells; D008168:Lung / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000502:physiology; D012130:Respiratory Hypersensitivity / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase