Janus kinase 3: a novel target for selective transplant immunosupression.
Existing immunosuppressants inhibit lymphocyte activation and T cell cytokine signal transduction pathways, reducing the rate of acute rejection episodes to < 10%. However, the widespread tissue distribution of their molecular targets engenders pleiotropic toxicities. One strategy to address this problem seeks to identify compounds that selectively inhibit a target restricted in distribution to the lymphoid system. Janus kinase (Jak) 3 is such a molecule; it mediates signal transduction via the gamma common chain of lymphokine surface receptors. Disruption of this lymphoid-restricted enzyme would not be predicted to produce collateral damage in other organ systems. Development of selective Jak3 inhibitors has been difficult due to crossreactivity with its homologue, Jak2. In contrast to all other putative antagonists, which are discussed in detail herein, one Jak3 inhibitor, NC1153, shows at least 40-fold greater selective inhibition for Jak3 than for Jak2, is robustly synergistic with calcineurin antagonists, and, either alone or in combination with cyclosporin, produces no adverse effects in rodents preconditioned to be at heightened risk for nephrotoxicity, bone marrow suppression, or altered lipid metabolism.
Podder
Hemangshu
H
The University of Texas Medical School at Houston, Division of Immunology and Organ Transplantation, 6431 Fannin Street, Suite 6.240, Houston, TX 77030, USA.
Kahan
Barry D
BD
D000595:Amino Acid Sequence; D000818:Animals; D004353:Drug Evaluation, Preclinical; D006084:Graft Rejection / Q000188:drug therapy / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D053631:Interleukin Receptor Common gamma Subunit; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects; D008252:Macaca fascicularis; D008352:Mannich Bases / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D011353:Prodigiosin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D018121:Receptors, Cytokine / Q000037:antagonists & inhibitors; D015375:Receptors, Interleukin-2 / Q000187:drug effects; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity
C119625:4-benzyloxy-5-((5-undecyl-2H-pyrrol-2-ylidene)methyl)-2,2'-bi-1H-pyrrole; C507941:IL2RG protein, human; C507942:Il2rg protein, mouse; D007166:Immunosuppressive Agents; D053631:Interleukin Receptor Common gamma Subunit; C507936:Jak3 protein, rat; D008352:Mannich Bases; C503557:NC 1153; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011758:Pyrroles; D018121:Receptors, Cytokine; D015375:Receptors, Interleukin-2; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507933:JAK3 protein, human; C507926:Jak2 protein, mouse; C507927:Jak2 protein, rat; C507935:Jak3 protein, mouse; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D011353:Prodigiosin