Selective inhibitor of Janus tyrosine kinase 3, PNU156804, prolongs allograft survival and acts synergistically with cyclosporine but additively with rapamycin

Abstract

Janus kinase 3 (Jak3) is a cytoplasmic tyrosine (Tyr) kinase associated with the interleukin-2 (IL-2) receptor common gamma chain (␥ c ) that is activated by multiple T-cell growth factors (TCGFs) such as IL-2, -4, and -7. Using human T cells, it was found that a recently discovered variant of the undecylprodigiosin family of antibiotics, PNU156804, previously shown to inhibit IL-2-induced cell proliferation, also blocks IL-2-mediated Jak3 auto-tyrosine phosphorylation, activation of Jak3 substrates signal transducers and activators of transcription (Stat) 5a and Stat5b, and extracellular regulated kinase 1 (Erk1) and Erk2 (p44/p42). Although PNU156804 displayed similar efficacy in blocking Jak3-dependent T-cell proliferation by IL-2, -4, -7, or -15, it was more than 2-fold less effective in blocking Jak2-mediated cell growth, its most homologous Jak family member. A 14-day alternate-day oral gavage with 40 to 120 mg/kg PNU156804 extended the survival of heart allografts in a dose-dependent fashion. In vivo, PNU156804 acted synergistically with the signal 1 inhibitor cyclosporine A (CsA) and additively with the signal 3 inhibitor rapamycin to block allograft rejection. It is concluded that inhibition of signal 3 alone by targeting Jak3 in combination with a signal 1 inhibitor provides a unique strategy to achieve potent immunosuppression. (Blood. 2002;99: 680-689)

Prevention of CD40-Triggered Dendritic Cell Maturation and Induction of T-Cell Hyporeactivity by Targeting of Janus Kinase 3

“…Hence Uckun and coworkers have demonstrated that administration of the rationally designed JAK3 inhibitor WHI-P-131/JANEX-1 attenuates acute GVHD in a fully mismatched mouse model (28). Using a chemically dissimilar JAK3 inhibitor, it was also found that allograft survival was significantly prolonged in a mouse model of heterotopic heart transplantation (29). Interestingly, JAK3 inhibition was effective in preventing diabetes in the NOD mouse (30).…”

The JAK/STAT pathway in rheumatoid arthritis: Pathogenic or protective?

“…To our knowledge, small molecule inhibitors of STATs have not yet been successfully developed. However, relatively selective inhibitors of JAK kinases already exist, and inhibition of protein tyrosine kinases has been effective in animal models and in the clinic (39)(40)(41)(42). It will be interesting to determine the effects of JAK/STAT pathway inhibitors on inflammatory arthritis.…”

Prodigiosin induces apoptosis of B and T cells from B-cell chronic lymphocytic leukemia

“…PNU156804 blocks IL-2-dependent NF-kB and AP-1 activation 26 and it is a selective inhibitor of Janus tyrosine kinase 3 (Jak3). 27 Cycloprodigiosin also inhibits NF-kB activation, 21 although prodigiosin does not. 23 Taken together, these results suggest that inhibition of these signaling pathways cannot explain the apoptotic activity of prodigiosins in B and T lymphocytes.…”