title: Discovery of potent and selective SH2 inhibitors of the tyrosine kinase ZAP-70.
abstract: 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.
authors.affiliation: ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, Massachusetts 02139-4234, USA.
authors.forename: C B
authors.initials: CB
authors.lastname: Vu
authors.forename: E G
authors.initials: EG
authors.lastname: Corpuz
authors.forename: T J
authors.initials: TJ
authors.lastname: Merry
authors.forename: S G
authors.initials: SG
authors.lastname: Pradeepan
authors.forename: C
authors.initials: C
authors.lastname: Bartlett
authors.forename: R S
authors.initials: RS
authors.lastname: Bohacek
authors.forename: M C
authors.initials: MC
authors.lastname: Botfield
authors.forename: C J
authors.initials: CJ
authors.lastname: Eyermann
authors.forename: B A
authors.initials: BA
authors.lastname: Lynch
authors.forename: I A
authors.initials: IA
authors.lastname: MacNeil
authors.forename: M K
authors.initials: MK
authors.lastname: Ram
authors.forename: M R
authors.initials: MR
authors.lastname: van Schravendijk
authors.forename: S
authors.initials: S
authors.lastname: Violette
authors.forename: T K
authors.initials: TK
authors.lastname: Sawyer
mesh_terms: 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
chemical_list: 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