Discovery of potent and selective SH2 inhibitors of the tyrosine kinase ZAP-70.
A series of 1,2,4-oxadiazole analogues has been shown to be potent and selective SH2 inhibitors of the tyrosine kinase ZAP-70, a potential therapeutic target for immune suppression. These compounds typically are 200-400-fold more potent than the native, monophosphorylated tetrapeptide sequences. When compared with the high-affinity zeta-1-ITAM peptide (Ac-NQL-pYNELNLGRREE-pYDVLD-NH(2), wherein pY refers to phosphotyrosine) some of the best 1,2, 4-oxadiazole analogues are approximately 1 order of magnitude less active. This series of compounds displays an unprecedented level of selectivity over the closely related tyrosine kinase Syk, as well as other SH2-containing proteins such as Src and Grb2. Gel shift studies using a protein construct consisting only of C-terminal ZAP-70 SH2 demonstrate that these compounds can effectively engage this particular SH2 domain.
Vu
C B
CB
ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, Massachusetts 02139-4234, USA.
Corpuz
E G
EG
Merry
T J
TJ
Pradeepan
S G
SG
Bartlett
C
C
Bohacek
R S
RS
Botfield
M C
MC
Eyermann
C J
CJ
Lynch
B A
BA
MacNeil
I A
IA
Ram
M K
MK
van Schravendijk
M R
MR
Violette
S
S
Sawyer
T K
TK
D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008958:Models, Molecular; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D000072377:Syk Kinase; D051746:ZAP-70 Protein-Tyrosine Kinase; D018909:src Homology Domains
D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D010069:Oxadiazoles; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; D051746:ZAP-70 Protein-Tyrosine Kinase