title: A Small Molecule Inhibitor of ITK and RLK Impairs Th1 Differentiation and Prevents Colitis Disease Progression.
abstract: In T cells, the Tec kinases IL-2-inducible T cell kinase (ITK) and resting lymphocyte kinase (RLK) are activated by TCR stimulation and are required for optimal downstream signaling. Studies of CD4(+) T cells from Itk(-/-) and Itk(-/-)Rlk(-/-) mice have indicated differential roles of ITK and RLK in Th1, Th2, and Th17 differentiation and cytokine production. However, these findings are confounded by the complex T cell developmental defects in these mice. In this study, we examine the consequences of ITK and RLK inhibition using a highly selective and potent small molecule covalent inhibitor PRN694. In vitro Th polarization experiments indicate that PRN694 is a potent inhibitor of Th1 and Th17 differentiation and cytokine production. Using a T cell adoptive transfer model of colitis, we find that in vivo administration of PRN694 markedly reduces disease progression, T cell infiltration into the intestinal lamina propria, and IFN-γ production by colitogenic CD4(+) T cells. Consistent with these findings, Th1 and Th17 cells differentiated in the presence of PRN694 show reduced P-selectin binding and impaired migration to CXCL11 and CCL20, respectively. Taken together, these data indicate that ITK plus RLK inhibition may have therapeutic potential in Th1-mediated inflammatory diseases.
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605; and.
authors.forename: Hyoung-Soo
authors.identifier: http://orcid.org/0000-0003-0899-8541
authors.initials: HS
authors.lastname: Cho
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605; and.
authors.forename: Hyun Mu
authors.identifier: http://orcid.org/0000-0001-5552-0597
authors.initials: HM
authors.lastname: Shin
authors.affiliation: Principia Biopharma, South San Francisco, CA 94080.
authors.forename: Helena
authors.initials: H
authors.lastname: Haberstock-Debic
authors.affiliation: Principia Biopharma, South San Francisco, CA 94080.
authors.forename: Yan
authors.identifier: http://orcid.org/0000-0002-7174-0482
authors.initials: Y
authors.lastname: Xing
authors.affiliation: Principia Biopharma, South San Francisco, CA 94080.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Owens
authors.affiliation: Principia Biopharma, South San Francisco, CA 94080.
authors.forename: Jens Oliver
authors.initials: JO
authors.lastname: Funk
authors.affiliation: Principia Biopharma, South San Francisco, CA 94080.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Hill
authors.affiliation: Principia Biopharma, South San Francisco, CA 94080.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Bradshaw
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605; and Leslie.Berg@umassmed.edu.
authors.forename: Leslie J
authors.identifier: http://orcid.org/0000-0001-6031-7542
authors.initials: LJ
authors.lastname: Berg
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D054418:Chemokine CCL20 / Q000235:genetics / Q000276:immunology; D054371:Chemokine CXCL11 / Q000235:genetics / Q000276:immunology; D003092:Colitis / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology
chemical_list: C493447:CCL20 protein, mouse; D054418:Chemokine CCL20; D054371:Chemokine CXCL11; C515203:Cxcl11 protein, mouse; D047428:Protein Kinase Inhibitors; D007371:Interferon-gamma; C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase