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The Mannich Base NC1153 Promotes Long-Term Allograft Survival and Spares the Recipient from Multiple Toxicities¹

Stanislaw M. Stepkowski^*, Judy Kao, Mou-Er Wang^*, Neelam Tejpal^*, Hemangshu Podder^*, Lucrezia Furian^*, Jonathan Dimmock, Amitabh Jha, Umashankar Das, Barry D. Kahan^* and Robert A. Kirken^2,

^* Division of Immunology and Organ Transplantation, Department of Surgery, University of Texas Medical School at Houston, Houston, TX 77030; Department of Integrative Biology and Pharmacology, University of Texas Medical School at Houston, Houston, TX 77030; and College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

JAK3 is a cytoplasmic tyrosine kinase with limited tissue expression but is readily found in activated T cells. Patients lacking JAK3 are immune compromised, suggesting that JAK3 represents a therapeutic target for immunosuppression. Herein, we show that a Mannich base, NC1153, blocked IL-2-induced activation of JAK3 and its downstream substrates STAT5a/b more effectively than activation of the closely related prolactin-induced JAK2 or TNF--driven NF-B. In addition, NC1153 failed to inhibit several other enzymes, including growth factor receptor tyrosine kinases, Src family members, and serine/threonine protein kinases. Although NC1153 inhibited proliferation of normal human T cells challenged with IL-2, IL-4, or IL-7, it did not block T cells void of JAK3. In vivo, a 14-day oral therapy with NC1153 significantly extended survival of MHC/non-MHC mismatched rat kidney allografts, whereas a 90-day therapy induced transplantation tolerance (>200 days). Although NC1153 acted synergistically with cyclosporin A (CsA) to prolong allograft survival, it was not nephrotoxic, myelotoxic, or lipotoxic and did not increase CsA-induced nephrotoxicity. In contrast to CsA, NC1153 was not metabolized by cytochrome P450 3A4. Thus, NC1153 prolongs allograft survival without several toxic effects associated with current immunosuppressive drugs.

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