Oral Anti-interferon Program

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MPI-0485520 is our lead preclinical compound in our small-molecule anti-interferon program for autoimmune diseases. It has demonstrated proof of concept activity in an animal model of the autoimmune disease rheumatoid arthritis. A medicinal chemistry program of lead optimization is ongoing to select a candidate compound for IND-enabling studies.

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Oral Anti-interferon Program for the treatment of Autoimmune Diseases

MPI-0485520 is an orally-available small molecule that potently and selectively inhibits IκB-kinase-ε (IKKε) and TANK-binding kinase 1 (TBK1) and is our lead preclinical compound in our small molecule anti-interferon program for autoimmune diseases [1][2]. MPI-0485520 exhibits high oral bio-availability, favorable ADME/PK properties and efficacy in an in vivo mouse model of rheumatoid arthritis [1][3]. In cellular models of type I interferon production, MPI-0485520 potently inhibits induction of type I interferons (IFNα/β) following stimulation of a variety of receptors that mediate the type-I interferon to pathogens, such as TLR3, TLR4, RIG-I, and MDA-5. Inhibition of other proinflammatory cytokines is also observed [1][2].

Inhibition of type I interferon production by IKKε /TBK1 inhibitors may benefit patients with autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus (SLE), scleroderma, Sjögren's syndrome, and polymyositis. Studies in in vivo models have additionally demonstrated a role for IKKε in the pathology of rheumatoid arthritis [4]. In April 2011, results from our most recent preclinical studies of MPI-0485520 were presented at the European League Against Rheumatism (EULAR) Annual European Congress of Rheumatology in London. In a proof of concept study, in the well characterized collagen-induced mouse model of arthritis [7], mice treated with MPI-0485520 show a dose-dependent and statistically significant reduction in the severity of clinical symptoms and paw and joint histopathology, as well as lower weight loss compared to control mice [3]. MPI-0485520 is one compound out of an extensive portfolio of potent and selective IKK epsilon/TBK1 inhibitors identified by our oral anti-interferon program. A medicinal chemistry program of lead optimization is ongoing to select a candidate compound for IND-enabling studies.

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About IKKε/TBK1

A number of autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, psoriasis, inflammatory bowel disease, scleroderma, Sjögren's syndrome, and polymyositis are characterized by overproduction of type I interferons and the generation of anti-nuclear autoantibodies. Upregulation of type I interferons occurs in response to bacterial and viral nucleic acids present during infection. This interferon response is dependent in part on the IκB-kinase-related proteins, IKKε and TBK1. In addition to foreign nucleic acids, recent studies have demonstrated that accumulation of endogenous human nucleic acids, which result from improper disposal of extracellular or intracellular DNA and RNA, can also generate a type I interferon response [5] [6].

Activation of IKKε and TBK1, via the membrane localized toll-like receptor TLR3 or cytoplasmic nucleic acid receptors (MDA5, RIG-1, DAI, and others), results ultimately, via activation of IKKε/TBK1, in the phosphorylation of interferon regulatory transcription factors 3 and 7 (IRF3/7). These receptors are part of the so-called innate immune pathway receptors and it is becoming increasingly clear that this pathway is sometimes inappropriately activated by endogenous nucleic acids leading to production of type I interferons and to the symptoms of autoimmune diseases.

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IKKε/TBK1 Activation Leads to Interferon α and β Production. Cellular receptors recognize bacterial and viral components and signal to activate the IKK-related protein kinases IKKε and TBK1. Toll-like receptor 3 (TLR3) binds endosomal dsRNA and TLR4 binds bacterial lipopolysaccharide (LPS). Cytoplasmic nucleic acid receptors RIG-I and MDA-5 recognize dsRNA while DAI and a still unknown receptor recognize dsDNA. Activated IKKε and TBK1 phosphorylate interferon regulatory factors 3 and 7 (IRF3/7) which upregulate transcription of the interferon α and β genes.

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Recent Presentations
MPI-0485520, a Small Molecule Inhibitor of IKKε/TBK1 is Active In a Mouse Collagen-Induced Arthritis Model pdf-icon-small
May 25-28, 2011
EULAR European Congress of Rheumatology
London, UK
385 KB
mpi-0485520-ACR-2010

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References

1. Richards B et al. Cellular and In Vivo Properties of MPI-0485520, a Novel and Potent Small Molecule Inhibitor of IKKε. FASEB 2010 Annual Meeting. Poster PDFpdf-icon-small

2. Richards B et al. Inhibition of Cytosolic Nucleic Acid Receptor Pathways Using the Small Molecule IKKepsilon/TBK1 Kinase Inhibitor. 2010 Annual Meeting of the American College of Rheumatology. Poster PDF pdf-icon-small

3. Richards B et al. MPI-0485520, a Small Molecule Inhibitor of IKKε/TBK1 is Active In a Mouse Collagen-Induced Arthritis Model. 2011 EULAR Annual European Congress of Rheumatology. Poster PDF pdf-icon-small

4. Corr M, Boyle DL, Ronacher L, Flores N, Firestein GS. 2009. Synergistic benefit in inflammatory arthritis by targeting I kappaB kinase epsilon and interferon beta. Ann Rheum Dis. 68:257-63. Free PMC Article pdf-icon-small

5. Lövgren T, Eloranta ML, Båve U, Alm GV, Rönnblom L. 2004. Induction of interferon-alpha production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG. Arthritis Rheum. 50:1861-72.  Free Article pdf-icon-small

6. Stetson DB, Ko JS, Heidmann T, Medzhitov R. 2008. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell. 134:587-98.  Free PMC Article pdf-icon-small

7. Bendele A. et al. Animal models of arthritis: relevance to human disease. Toxicol Pathol. 1999 Jan-Feb;27(1):134-42. Free Article pdf-icon-small

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