It has been well established that while the Hispanic population comprises slightly greater than 10% of the US population, they account for a disproportionately higher percentage of disease when compared to non-Hispanic whites. This includes certain types of cancer, stroke as well as coronary heart disease, diabetes and liver disease. The latter three conditions often require transplantation of key organs as the only treatment option. A major complication to treating these patients is that all transplantation immunotherapies are limited due to high drug toxicity. It is therefore a critical need to identify new therapeutic strategies to achieve effective long-term acceptance of these grafts to address the health disparities issues currently incurred by the Hispanic community. This application and its research seek to reverse this dire situation. Unlike the majority of the current immunosuppressive regimes that target early T-cell signaling pathways (e.g. CsA or FK506), new evidence suggest that targeting late T-cell signaling pathways by disrupting the Janus tyrosine kinase (Jak) 3 pathway is a viable option. Indeed studies in both humans and mice have shown that genetic dysfunction of either Jak3 or its receptor, the common IL2 receptor-(, results in an inactivated immune system. Thus Jak3 represents a novel molecular target for the treatment of T-cell immune mediated disorders. The complication in this process is to identify a molecule that selectively disrupts Jak3 and not its closest homologue Jak2, in which the later enzyme is critical for red blood cell development. Inactivation of Jak3, but not Jak2, represents a major obstacle to the pharmaceutical industry to achieve immune suppression, in the case of transplantation, without producing severe anemia. Here we propose that a novel Jak3 inhibitor developed by Dr. Kirken's group, NC1153, harbors significant clinical potential for T-cell immune mediated disorders. With these Phase 1 SBIR funds EP Pharma seeks to accomplish the following three specific aim;1) test a small library of molecules derived from the parent compound (NC1153) for a more efficacious agent;2) validate its high selectivity for Jak3 as opposed to other kinases and 3) determine potential toxic effects on off-target cells. We expect that this work will provide a novel therapeutic compound to treat several diseases with higher incidence rates in Hispanics, but also have applications to other minority and non-minority patients, and will be developed during the Phase II SBIR.
The objective of this proposal is to develop a novel immunosuppressive agent for the prevention of transplanted organ rejection, a condition that strongly impacts the Hispanic population. For many in the Hispanic population that suffers from cardiovascular disease, liver disease and diabetes, receiving a transplanted organ is their only treatment option. Unfortunately, currently used immunosuppressive agents have limited activity and are associated with a variety of toxic side effects. Our novel drug candidate has the potential to overcome many of these obstacles and result in better therapy for this and other T-cell mediated diseases.
| Ross, J A; Spadaro, M; Rosado, D C et al. (2014) Inhibition of JAK3 with a novel, selective and orally active small molecule induces therapeutic response in T-cell malignancies. Leukemia 28:941-4 |
