Janus tyrosine kinase 3 inhibition for the prevention of transplant rejection
SummaryTransplantation immunotherapy commonly involves the use of azathioprine often combined with low doses of cyclosporine. Increased susceptibility to infection and severe toxicity represent serious adverse effects and a newer molecular target being investigated for the prevention of transplant rejection is Janus tyrosine kinase 3 (Jak3). Jak3 is this months "Target of the Month" from LeadDiscovery's and here they describe Pfizer's efforts to optimize inhibitors of this kinase
The global market for immunosuppressant therapy is in excess of 4 billion USD per year. This therapeutic class is used for the treatment of both autoimmune diseases (see our recent analysis of rheumatoid arthritis therapeutics) and for the prevention of organ rejection in transplantation.
Since the first successful kidney transplantation more than 40 years ago, the treatment of end-stage organ failure has dramatically improved. Many organs are now transplanted, the most common of which include (procedures performed in the US in 2001) the kidney (14,000), heart (2,000), liver (5,000) and lung (1,000). Despite these figures transplantation is still somewhat limited, mainly because of rejection which can destroy the tissue soon after transplantation or over a more prolonged time frame. Limitations in the availability of human donor organs also continue to be important.
Host vs graft reaction is the principal mechanism of acute rejection and causes graft destruction days to months after transplantation. This reaction is characterized histologically by mononuclear cellular infiltration of the allograft, with varying degrees of hemorrhage and edema. After resolution of acute rejection, the allograft commonly survives for prolonged periods, even though immunosuppressive drug dosages are reduced to very low levels. Chronic rejection often progresses insidiously despite increased immunosuppressive therapy. It is thought to be due, in large part, to antibody-mediated damage. The pathologic picture differs from that of acute rejection. The arterial endothelium is primarily involved, with extensive proliferation that may gradually occlude the vessel lumen, resulting in ischemia and fibrosis of the graft.
Immunosuppressants are used to control rejection and are primarily responsible for the success of transplantation. Immunotherapy commonly involves the use of azathioprine beginning at the time of transplantation often combined with low doses of cyclosporine. However, immunosupressants suppress all immunologic reactions, thus making overwhelming infection the leading cause of death in transplant recipients. In addition immunosupressants are associated with severe toxicity.
The most significant complications of drugs used for transplant patients include nephrotoxicity, neurotoxicity, new-onset post-transplant diabetes mellitus, hyperlipidemia, and hypertension. These side effects occur in part because the molecular targets of currently used immunosuppresants are ubiquitously expressed. A molecular target recently receiving interest is the cytoplasmic localized Janus tyrosine kinase 3 (Jak3) which is activated by multiple cytokines, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 through engagement of the IL-2R common gamma-chain. JAK3 is primarily expressed in T and B cells and plays a critical role in T cell development and function. Inhibition of this enzyme therefore represents a selective target for new generation immunosuppressants.
In their recent article Changelian et al describe how the screening of Pfizer’s chemical library for inhibitors of JAK3 kinase activity provided the lead compound, CP-352,664. Extensive chemical modification led to the development of CP-690,550. Although CP-690,550 demonstrated low nanomolar potency for JAK3 inhibition, it was 20- to 100-fold less potent for JAK2 and JAK1 and failed to inhibit a large panel of other kinase. JAK2 mediates signaling via many hematopoietic cytokines, and this selectivity is expected to confer less anemia, thrombocytopenia, and leukopenia as compared to less selective molecules.
Cell-based assays demonstrated that CP-690,550 inhibited JAK3 mediated IL-2–induced T cell proliferation with 30-fold greater potency than its effects on JAK2-mediated events. In vivo efficacy of CP-690,550 was then determined in a murine model of heterotopic heart transplantation. All animals treated with vehicle alone rejected their allografts within 12 days. In contrast, dosing with CP-690,550 resulted in a dose-dependent increase in survival of transplanted hearts. This effect was extended past the drug administration period such that treatment for 28 days resulted in animals surviving for a median of greater than 60 days.
A second non-human primate model of kidney transplantation was then used to confirm the efficacy of CP-690,550. Vehicle control animals rapidly rejected transplanted kidney. CP-690,550 treatment extended graft survival by ten-fold and increased survival even more effectively than clinically relevant doses of the reference compound cyclosporin A. Dose-limiting side effects associated with current anti-rejection were not seen although anemia was observed at high doses.
This study therefore supports the further development of CP-690,550 and other JAK3 inhibitors. Groups interested in this field should be aware of the Kinase Enterprise Library currently featured by LeadDiscovery and which represents an assay ready collection of candidate kinase inhibitors (Click here for details). Screening of this library may allow the development of further JAK3 inhibitors.
For further details on this work please click here