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.
Public Health Relevance: 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.
Thesaurus Terms: 2h-1,3,2-Oxazaphosphorin-2-Amine, N,N-Bis(2-Chloroethyl)Tetrahydro-, 2-Oxide;2h-1,3,2-Oxazaphosphorin-2-Amine, N,N-Is(2-Chloroethyl)Tetrahydro-,2-Oxide;Atp[{..}]protein-Tyrosine O-Phosphotransferase;Accounting;Address;Adrenal Cortex Hormones;Adverse Effects;Affect;Allografting;Anemia;Apoplexy;Assay;Autoimmune Diseases;Bioassay;Biologic Assays;Biological Assay;Blood Erythrocyte;Blood Normocyte;Body Tissues;Bone Marrow Transplant;Bone Marrow Transplantation;Ctx;Cyclo-Cell;Cardiovascular Diseases;Carloxan;Cell Communication And Signaling;Cell Function;Cell Line;Cell Lines, Strains;Cell Process;Cell Signaling;Cell Physiology;Cellline;Cells;Cellular Function;Cellular Physiology;Cellular Process;Cerebral Stroke;Cerebrovascular Apoplexy;Cerebrovascular Stroke;Cerebrovascular Accident;Chronic;Ciclofosfamida;Ciclofosfamide;Ciclosporin;Cicloxal;Clafen;Claphene;Clinical;Clinical, Transplantation, Organ;Co-Stimulator;Common Rat Strains;Complication;Coronary Disease;Coronary Heart 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System;Immunologically Directed Therapy;Immunosuppressants;Immunosuppression Effect;Immunosuppressions (Physiology);Immunosuppressive Agents;Immunosuppressive Effect;Immunotherapy;Incidence;Industry, Pharmaceutic;Interleukin 2;Interleukin 2 Precursor;Interleukin 2 Receptor;Interleukin Ii;Interleukin-2;Interleukine 2;Interleukine 2 Precursor;Interleukine Ii;Intracellular Communication And Signaling;Investigation;Jak-3;Jak3;Jak3 Protein;Janus Kinase 3;Kinases;Latino Population;Lead;Ledoxina;Libraries;Liver Diseases;Lymphocyte Mitogenic Factor;Mammals, Mice;Mammals, Rats;Man (Taxonomy);Man, Modern;Mannich Bases;Marrow Transplantation;Marrow Erythrocyte;Mediating;Medication;Mice;Minority;Mitogenic Factor;Mitoxan;Molecular Target;Murine;Mus;Natural Immunosuppression;Neosar;Non-Hispanic;Normal Cell;Not Hispanic Or Latino;Oral;Organ;Organ Transplantation;Organ Transplants;Organ Transplants, Including Bone Marrow For Dct;Ptk;Ptk Receptors;Parents;Pathway Interactions;Patients;Pattern;Pb 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Factor;T-Cells;T-Lymphocyte;Tcgf Receptors;Testing;Therapeutic;Therapeutic Corticosteroid;Threonine Kinase;Thymocyte Stimulating Factor;Thymus-Dependent Lymphocytes;Tissues;Toxic Effect;Toxicities;Transmembrane Receptor Protein Tyrosine Kinase;Transphosphorylases;Transplantation;Transplantation Surgery;Transplantation Tolerance;Treatment Efficacy;Treatment Side Effects;Tyrosine Kinase;Tyrosine Kinase Growth Factor Receptor;Tyrosine Kinase Linked Receptors;Tyrosine Kinase Receptors;Tyrosine-Protein Kinase Receptor Eek;Tyrosine-Specific Protein Kinase;Tyrosylprotein Kinase;Vascular Accident, Brain;Work;Zytoxan;Analog;Autoimmune Disorder;Biological Signal Transduction;Blood Corpuscles;Body System, Allergic/Immunologic;Brain Attack;Cancer Progression;Cancer Type;Cardiovascular Disorder;Cerebral Vascular Accident;Combinatorial Chemistry;Coronary Disorder;Cultured Cell Line;Diabetes;Disease /Disorder;Disease/Disorder;Dosage;Drug /Agent;Drug Candidate;Drug/Agent;Experience;Genetics;Health 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