Novel Small Molecule Inhibitor of Rheumatoid Arthritis

DESCRIPTION (provided by applicant): Lck is a Src family non-receptor tyrosine kinase expressed by T lineage lymphocytes. In T cells, Lck plays an essential role in the generation of antigen-mediated activation signals. Since T cell activation is central to mounting immune response, inhibition of Lck blocks T cell activation and suppresses the immune response. Accordingly, Lck serves as an ideal target for the development of novel immunosuppressant agents. Motivated by these biological properties, a combined computer-aided drug design (CADD) and experimental program was undertaken to identify novel Lck inhibitors. Targeting the pY+3 region of the SH2 domain of Lck a series of Lck inhibitors have been discovered. A subset of these compounds has been shown to be specific for Lck versus other SH2 domain containing Src family kinases with affinities for Lck in the low micromolar range. These Lck selective compounds inhibited mixed lymphocyte reaction in vitro, and popliteal lymph node local allogeneic responses in mice and adjuvant arthritis, a rat experimental model of rheumatoid arthritis in vivo. These compounds have therapeutic potential as immunosuppressants/modulators. In this application we propose to determine the rank order of these compounds for their therapeutic efficacy. The goal of this Phase I project is to select which lead compound for synthetic chemistry lead optimization to be proposed in a Phase II SBIR application. The ultimate goal is an FDA IND submission of a drug candidate for Phase I clinical trials in rheumatoid arthritis, MS or other chronic inflammatory diseases. PUBLIC HEALTH RELEVANCE: Rheumatoid arthritis (RA) is a chronic inflammatory disease of high prevalence in the U.S. and the other major developed countries, affecting over 2 million U.S. citizens, resulting in over 3 billion in medical costs and other indirect expenses annually. The treatment of RA includes traditional pharmacological agents as well as breakthrough biologics, e.g. targeting TNF alpha. The TNF blockers have increased efficacy in a subset of patients but the costs of these drugs are in excess of 10,000 - 20,000 per year. Other chronic inflammatory diseases such as multiple sclerosis also are treated by these high cost biological therapeutics. There is a significant unmet medical need for drugs with increased efficacy in a larger proportion of patients and that are more cost effective. The specific aims of this project are designed to identify a lead compound with the biological efficacy, potency and safety suitable for subsequent lead optimization and in-depth evaluation in disease-relevant animal models, safety pharmacology and toxicology. The ultimate goal is development of an effective drug candidate for these chronic inflammatory diseases that will be substantially more cost effective than the breakthrough biologics.