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.

An Extremely Simple Dibenzopentalene Synthesis from 2‐Bromo‐1‐ethynylbenzenes Using Nickel(0) Complexes: Construction of Its Derivatives with Various Functionalities

“…Trimethylsilylacetylene was purchased from Shin-Etsu Chemical Co., Ltd. Compounds 9 [15] and 16, [16] 3-bromo-4-iodotoluene, [17] 4-bromo-5-iodo-1,2-dimethoxybenzene, [18] and methyl 3-bromo-4-iodobenzoate [19] were prepared according to previously reported procedures.…”

Oxadiazoles

“…Another different general synthetic route is based on the 1,3-dipolar cycloaddition of nitrile oxides to nitriles, developed by Leandri (cycloaddition route) [180]. The cyclization of O-acylamidoximes is performed by heating them at their melting point [185], or at reflux in a high-boiling solvent (DMF [186], toluene [187], pyridine [188], ethanol [189], acetonitrile [190], glacial acetic acid at reflux) [191,192], eventually in the presence of a dehydrating agent (phosphorous pentoxide, phosphorus oxychloride, or acetic anhydride).…”

“…Compounds 367 contain, at C5 of the 1,2,4-oxadiazole nucleus, a residue of an amino group linked to peptide moieties, and a carboxyl or ester functionality attached at C3 directly or through a methylene chain [293], and 5-HT1D (5-hydroxytryptamine) receptors [294], and as antagonists for 5-HT [295] or histamine H3 receptors [296]. They show activity as antirhinoviral agents [297], growth hormone secretagogues [298], anti-inflammatory agents [234], and antitumor agents [183,188,299]. They also inhibit the SH2 domain of tyrosine kinase [300], monoamine oxidase [301], human neutrophil elastase [302], and human DNA topoisomerases.…”

Synthesis, analgesic and anti-inflammatory activities of novel 3-(4-acetamido-benzyl)-5-substituted-1,2,4-oxadiazoles

“…Due to increased hydrolytic [11] and metabolic stabilities of the oxadiazole ring, improved pharmacokinetic and in vivo performance is often observed, which make these heterocycles an important structural motif for the pharmaceutical industry. As a consequence of these characteristics, oxadiazoles have impacted numerous drug discovery programs including muscarinic agonists [12], benzodiazepine receptor partial agonists [13], dopamine transporters [14], anti-rhinovirals [15], growth hormone secretogogues [16], 5-HT agonists [17], antispasmodics [18], nematocidal, fungicidal and microbicides [19], analgesics [20], anti-inflammatory agents [21], Fab I inhibitors as antibacterial agents [22], immunosuppressants [23], and also antiplatelet and antithrombotic agents [24]. 3-Aryl-5-substituted 1,2,4-oxadiazoles have also shown the activity against kinetoplastid parasites [25] and interleukin-8 (IL-8) receptor antagonists and thereby leading to unique anti-inflammatory agents [26].…”