New immunosuppressive drug PNU156804 blocks IL-2-dependent proliferation and NF-kappa B and AP-1 activation

We had previously shown that the drug undecylprodigiosin (UP) blocks human lymphocyte proliferation in vitro. We have now investigated the mechanism o f action of a new analogue of UP, PNU156804, which shows a more favorable a ctivity profile than UP in mice. We demonstrate here that the biological ef fect of PNU156804 in vitro is indistinguishable from UP: PNU156804 blocks h uman T cell proliferation in mid-late G(1), as determined by cell cycle ana lysis, expression of cyclins, and cyclin-dependent kinases and retinoblasto ma phosphorylation, In addition, we show that PNU156804 does not block sign ificantly the induction of either IL-2 or IL-2R alpha- and gamma-chains but inhibits IL-2-dependent T cell proliferation. We have investigated several molecular pathways that are known to be activated by IL-2 in T cells. We s how that PNU156804 does ndt inhibit c-myc and bcl-2mRNA induction. On the o ther hand, PNU156804 efficiently inhibits the activation of the NF-kappa B and AP-1 transcription factors. PNU156804 a inhibition of NF-kappa B activa tion is due to the inhibition of the degradation of I kappa B-alpha and I k appa B-beta, PNU156804 action is restricted to some signaling pathways; it does not affect:NF-kappa B activation by PMA in T cells but blocks that ind uced by CD40 cross-linking in B lymphocytes, We conclude that the prodigios in family of immunosuppressants is a new family:of molecules that show a no vel target specificity clearly: distinct from that of other immunosuppressi ve drugs-such as cyclosporin A, FK506; and rapamycin.