A-770041, a Novel and Selective Small-Molecule Inhibitor of Lck, Prevents Heart Allograft Rejection

Abstract

Lck, one of eight members of the Src family of tyrosine kinases, is activated after T cell stimulation and is required for T-cell proliferation and interleukin (IL)-2 production. Inhibition of Lck has been a target to prevent lymphocyte activation and acute rejection. Here, we report the pharmacologic characterization of 1-methyl-1H-indole-2-carboxylic acid, an orally bioavailable pyrazolo [3,4-d]pyrimidine with increased selectivity for Lck compared with previously reported compounds.

Expression of lymphocyte coding genes in peripheral blood and lymphocyte infiltration in cardiac tissues influenced by cyclosporin A in heterotopic heart transplantation model in rats

“…P59Fyn phosphorylates tyrosines on the substrate and activates and recruits ZAP-70, which phosphorylates SLP-76 joint protein to activate the Ras-Mitogen path which activates IP3, DG second message path [17][18][19]. These experimental results showed that in the early stage of transplantation, unlike CD4 and CD8 mRNA expression, P59Fyn mRNA was in a hyperactivation state at 72 h, which was independent of CD4 and CD8 gene transcription in the control group.…”

“…However, many reports showed that acute rejection occurred after medication [15][16][17]. We wanted to observe the effects of cyclosporine A on lymphocyte proteins, gene expression kinetics and pathological changes occurring after heart transplant.…”

Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation

“…This may be the most relevant finding in our results because it opens the opportunity to titrate concentrations of each individual drug below toxicity levels while maintaining the ability to quell aberrant T-cell activation. Further studies combining Lck inhibitors, such as dasatinib or the recently described A-770041, 43,44 with costimulatory blockade may also provide new routes to achieve desired levels of immunomodulation while minimizing side effects. Therefore, new dosing schedules could be developed to optimize SFK inhibition in the context of concurrent NFAT, mTOR, or JAK inhibition.…”

Impact of Exogenous Galectin-9 on Human T Cells

“…To confirm this observation by an independent approach, we applied a chemical inhibitor of Lck, A-770041, on wild-type (WT) Jurkat cells (41). This chemical compound is 300-fold more selective against Lck (IC 50 ϭ 147 nM) than against Fyn (IC 50 ϭ 44.1 M), another Src family tyrosine kinase involved in T cell signaling (41). As expected, the calcium influx induced by gal-9 was markedly reduced by increasing concentrations of Lck inhibitor and was totally abolished with 170 nM (Fig.…”

“…Therefore, Lck seemed important for the gal-9 transduction pathway. To confirm this observation by an independent approach, we applied a chemical inhibitor of Lck, A-770041, on wild-type (WT) Jurkat cells (41). This chemical compound is 300-fold more selective against Lck (IC 50 ϭ 147 nM) than against Fyn (IC 50 ϭ 44.1 M), another Src family tyrosine kinase involved in T cell signaling (41).…”