LX2931 & LX2932
Status
LX2931: Phase 1
LX2932: Preclinical studies
Indications
Rheumatoid Arthritis and other autoimmune diseases
Overview
LX2931 and LX2932 are orally-delivered, small molecules for the potential treatment of autoimmune diseases such as rheumatoid arthritis.
Inappropriate activation of lymphocytes is associated with autoimmune diseases, wherein the immune system malfunctions and causes the body to attack its own organs, tissues, and cells. LX2931 and LX2932 are intended to regulate lymphocytes in the body during an inflammatory response.
Principal Targets
The target for LX2931 and LX2932 is sphingosine-1-phosphate lyase (S1P Lyase), an enzyme in the sphingosine-1-phosphate (S1P) pathway associated with inflammatory response. From research conducted in the Genome5000 project, Lexicon scientists discovered that mice lacking this enzyme have increased retention of immune cells in the thymus and spleen with a corresponding reduction in the deployment of T-cells and B-cells into the circulating blood.
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LX2931 (and LX2932) regulates lymphocytes by targeting S1P lyase, the enzyme that degrades S1P. The secreted messenger, S1P, interacts with S1P receptors such as S1P1 (aka EDG1) to regulate lymphocyte migration from lymphoid tissues (e.g., thymus and spleen). Inhibition of S1P lyase by LX2931 (and LX2932) causes the concentration of S1P to rise in lymphoid tissues, thereby causing lymphocytes to be retained in the lymphoid tissues. |
Preclinical Data
In preclinical studies, LX2931 produced a consistent reduction in circulating lymphocyte counts in multiple species. In addition, LX2931 reduced joint inflammation and prevented arthritic destruction of joints in mouse models of arthritis. LX2932 is in preclinical studies as a backup molecule to the LX2931 compound; initial studies demonstrated that LX2932 treatment produces a consistent reduction in lymphocyte counts in multiple species.
Clinical Status
Lexicon initiated Phase 1 clinical trials in December 2007 to evaluate the safety, tolerability and pharmacokinetics of LX2931 following single oral doses. Total lymphocyte counts as well as specific T-cell and B-cell subpopulations will be evaluated in a double-blind, randomized, placebo controlled study.
Related Publications
Hait, N. C., C. A. Oskeritzian, S. W. Paugh, S. Milstien, and S. Spiegel. 2006.
Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases.
Biochim. Biophys. Acta. 1758: 2016-2026.
Pyne, S., and N. J. Pyne. 2000.
Sphingosine 1-phosphate signalling in mammalian cells.
Biochem. J. 349: 385-402.
Cyster, J. G. 2005.
Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs.
Annu. Rev. Immunol. 23: 127-159.
Schwab, S. R., J. P. Pereira, M. Matloubian, Y. Xu, Y. Huang, and J. G. Cyster. 2005.
Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients.
Science. 3091: 1735-1739.
Pettus, B. J., C. E. Chalfant, and Y. A. Hannun. 2004.
Sphingolipids in inflammation: roles and implications.
Curr. Mol. Med. 4: 405-418.
Chun, J., and H. Rosen. 2006.
Lysophospholipid receptors as potential drug targets in tissue transplantation and autoimmune diseases.