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OP0195 Genetic and Pharmacologic Inhibition of MST1 Blocks Lymphocyte Function and Protects Against Inflammation and Autoimmunity
  1. T. Oravecz1,
  2. W. C. Chang1,
  3. K. G. Jhaver1,
  4. A. Al-Shami1,
  5. T. C. Jessop1,
  6. B. Hamman1,
  7. J. T. Bagdanoff1,
  8. D. J. Augeri1,
  9. P. Vogel1,
  10. J. Swaffield1,
  11. A. Wilson1,
  12. K. G. Carson1,
  13. A. Main1,
  14. B. P. Zambrowicz1
  1. 1Lexicon Pharmaceuticals, Inc., The Woodlands, Texas, United States

Abstract

Background The mammalian sterile 20-like kinase 1 (MST1) is a MAP4 kinase which acts upstream of a wide range of signal transduction pathways. It can modify signaling events mediated by Jnk, p38, histone 2B, hSav, FOXO3, and LFA-1; therefore it is involved in diverse cellular responses, including apoptosis, oxidative stress, integrin LFA-1 clustering, and lymphocyte adhesion and trafficking (1-3).

Objectives We have explored the contribution of MST1 to immune function and disease development by performing a comprehensive phenotypic analysis of MST1-deficient (-/-) mice and challenging them in various disease models. We have also discovered potent inhibitors of MST1 and assessed their potential therapeutic utility in mouse models of arthritis.

Methods Details of the phenotypic analysis applied to knockout lines generated in our facilities is described in Reference 4. It includes complete blood cell counts and phenotyping, in vitro cell activation assays, and in vivo challenges to assess immune system function during disease development.

Results MST1-/- mice exhibited marked lymphopenia in the blood and peripheral lymphoid tissues compared to wild type littermates. Absence of MST1 reduced CD3/CD28-mediated in vitro T-cell proliferation and cytokine production, blocked cell cycle progression, elevated apoptosis of T cells, and altered expression of T-cell activation markers. In addition, MST1-/- B cells showed decreased responses to B-cell mitogens in vitro and deficient anti-ovalbumin Ig production in vivo. Consistent with altered T- and B-cell function, MST1 knockout mice were resistant to disease induction in a number of autoimmune and inflammatory disease models, including collagen-induced and anti-collagen antibody-induced arthritis. These findings have prompted the discovery of novel compounds that are potent inhibitors of MST1 and exhibit oral bioavailability. Administration of these compounds to mice recapitulated the disease-resistant phenotype of MST1-deficient mice.

Conclusions MST1 controls multiple aspects of lymphocyte physiology and is essential for disease induction in a number of autoimmune and inflammatory disease models.

References

  1. Nehme NT, et al. Blood. 119:777-85, 2012.

  2. Mou F, et al. J. Exp. Med. 209:741-59, 2012.

  3. Avruch J, et al. Semin. Cell. Dev. Biol. 23:770-84, 2012.

  4. Beltrandelrio H et al. in Model Organisms in Drug Discovery. P. M. Carroll, and K. Fitzgerald, eds. John Wiley & Sons, Chichester, United Kingdom, pp. 251–278, 2003.

Disclosure of Interest T. Oravecz Shareholder of: Lexicon Pharmaceuticals, Inc., Employee of: Lexicon Pharmaceuticals, Inc., W. Chang Shareholder of: Lexicon Pharmaceuticals, Inc., Employee of: Lexicon Pharmaceuticals, Inc., K. Jhaver Shareholder of: Lexicon Pharmaceuticals, Inc., Employee of: Lexicon Pharmaceuticals, Inc., A. Al-Shami Shareholder of: Lexicon Pharmaceuticals, Inc., Employee of: Lexicon Pharmaceuticals, Inc., T. Jessop Shareholder of: Lexicon Pharmaceuticals, Inc., Employee of: Lexicon Pharmaceuticals, Inc., B. Hamman Shareholder of: Lexicon Pharmaceuticals, Inc., Employee of: Lexicon Pharmaceuticals, Inc., J. Bagdanoff Shareholder of: Lexicon Pharmaceuticals, Inc., Employee of: Lexicon Pharmaceuticals, Inc., D. Augeri Shareholder of: Lexicon Pharmaceuticals, Inc., Employee of: Lexicon Pharmaceuticals, Inc., P. Vogel Shareholder of: Lexicon Pharmaceuticals, Inc., Employee of: Lexicon Pharmaceuticals, Inc., J. Swaffield Shareholder of: Lexicon Pharmaceuticals, Inc., Employee of: Lexicon Pharmaceuticals, Inc., A. Wilson Shareholder of: Lexicon Pharmaceuticals, Inc., Employee of: Lexicon Pharmaceuticals, Inc., K. Carson Shareholder of: Lexicon Pharmaceuticals, Inc., Employee of: Lexicon Pharmaceuticals, Inc., A. Main Shareholder of: Lexicon Pharmaceuticals, Inc., Employee of: Lexicon Pharmaceuticals, Inc., B. Zambrowicz Shareholder of: Lexicon Pharmaceuticals, Inc., Employee of: Lexicon Pharmaceuticals, Inc.

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