Discovery and SAR of 2-amino-5-[(thiomethyl)aryl]thiazoles as potent and selective Itk inhibitors.
A series of structurally novel aminothiazole based small molecule inhibitors of Itk were prepared to elucidate their structure-activity relationships (SARs), selectivity and cell activity in inhibiting IL-2 secretion in a Jurkat T-cell assay. Compound 2 is identified as a potent and selective Itk inhibitor which inhibits anti-TCR antibody induced IL-2 production in mice in vivo.
Das
Jagabandhu
J
Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000, USA. jagabandhu.das@bms.com
Liu
Chunjian
C
Moquin
Robert V
RV
Lin
James
J
Furch
Joseph A
JA
Spergel
Steven H
SH
Doweyko
Arthur M
AM
McIntyre
Kim W
KW
Shuster
David J
DJ
O'Day
Kathleen D
KD
Penhallow
Becky
B
Hung
Chen-Yi
CY
Kanner
Steven B
SB
Lin
Tai-An
TA
Dodd
John H
JH
Barrish
Joel C
JC
Wityak
John
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000187:drug effects / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D019169:Jurkat Cells; D051379:Mice; D015394:Molecular Structure; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011948:Receptors, Antigen, T-Cell / Q000187:drug effects; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D013844:Thiazoles; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase