Characterization of isoquinolinium salt derivatives as potent inhibitors of transcription factor NFAT (33.20)

Abstract

Abstract Transcription factor NFAT plays critical roles in gene expression during the immune response. NFAT activation is regulated by calcineurin (CaN), a target of the immunosuppressive drugs such as cyclosporin A (CsA) and FK-506. CsA blocks phosphatase activity of CaN, which results in inactivation of NFAT. In search for novel immunosuppressive drug candidates, we have screened an organic chemical library and identified several isoquinolinium salt derivatives as novel inhibitors of NFAT. These compounds inhibited proliferation of peripheral blood mononuclear cell (PBMC) and T-lymphocytes by a mixed-lymphocyte reaction. Their inhibitory effect was specific to transcription factor NFAT, but in contrast with CsA, they neither affect the phosphatase activity of CaN nor nuclear localization of NFAT upon ionomycin stimulation. The DNA binding assay reveals that these compounds strongly attenuated DNA binding activity of NFAT. Taken together, these results indicate that these novel compounds inhibit NFAT activity without any significant change in CaN activity, which is a different mechanism from that of CaA, and suggest as potential candidates for immunosuppression