title: A restricted role for TYK2 catalytic activity in human cytokine responses revealed by novel TYK2-selective inhibitors.
abstract: TYK2 is a JAK family protein tyrosine kinase activated in response to multiple cytokines, including type I IFNs, IL-6, IL-10, IL-12, and IL-23. Extensive studies of mice that lack TYK2 expression indicate that the IFN-α, IL-12, and IL-23 pathways, but not the IL-6 or IL-10 pathways, are compromised. In contrast, there have been few studies of the role of TYK2 in primary human cells. A genetic mutation at the tyk2 locus that results in a lack of TYK2 protein in a single human patient has been linked to defects in the IFN-α, IL-6, IL-10, IL-12, and IL-23 pathways, suggesting a broad role for TYK2 protein in human cytokine responses. In this article, we have used a panel of novel potent TYK2 small-molecule inhibitors with varying degrees of selectivity against other JAK kinases to address the requirement for TYK2 catalytic activity in cytokine pathways in primary human cells. Our results indicate that the biological processes that require TYK2 catalytic function in humans are restricted to the IL-12 and IL-23 pathways, and suggest that inhibition of TYK2 catalytic activity may be an efficacious approach for the treatment of select autoimmune diseases without broad immunosuppression.
authors.affiliation: Department of Immunology, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Sue J
authors.initials: SJ
authors.lastname: Sohn
authors.forename: Kathy
authors.initials: K
authors.lastname: Barrett
authors.forename: Anne
authors.initials: A
authors.lastname: Van Abbema
authors.forename: Christine
authors.initials: C
authors.lastname: Chang
authors.forename: Pawan Bir
authors.initials: PB
authors.lastname: Kohli
authors.forename: Hidenobu
authors.initials: H
authors.lastname: Kanda
authors.forename: Janice
authors.initials: J
authors.lastname: Smith
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Lai
authors.forename: Aihe
authors.initials: A
authors.lastname: Zhou
authors.forename: Birong
authors.initials: B
authors.lastname: Zhang
authors.forename: Wenqian
authors.initials: W
authors.lastname: Yang
authors.forename: Karen
authors.initials: K
authors.lastname: Williams
authors.forename: Calum
authors.initials: C
authors.lastname: Macleod
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Hurley
authors.forename: Janusz J
authors.initials: JJ
authors.lastname: Kulagowski
authors.forename: Nicholas
authors.initials: N
authors.lastname: Lewin-Koh
authors.forename: Hart S
authors.initials: HS
authors.lastname: Dengler
authors.forename: Adam R
authors.initials: AR
authors.lastname: Johnson
authors.forename: Nico
authors.initials: N
authors.lastname: Ghilardi
authors.forename: Mark
authors.initials: M
authors.lastname: Zak
authors.forename: Jun
authors.initials: J
authors.lastname: Liang
authors.forename: Wade S
authors.initials: WS
authors.lastname: Blair
authors.forename: Steven
authors.initials: S
authors.lastname: Magnuson
authors.forename: Lawren C
authors.initials: LC
authors.lastname: Wu
mesh_terms: D000818:Animals; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D053759:Interleukin-23 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D053634:TYK2 Kinase / Q000276:immunology* / Q000378:metabolism*
chemical_list: D016207:Cytokines; D053759:Interleukin-23; D047428:Protein Kinase Inhibitors; D018664:Interleukin-12; D053634:TYK2 Kinase
references.citation: Immunol Rev. 2009 Mar;228(1):273-87
references.pmid: 19290934
references.citation: Nature. 1996 Jul 11;382(6587):171-4
references.pmid: 8700208
references.citation: J Biol Chem. 1995 Feb 17;270(7):3327-34
references.pmid: 7531704
references.citation: J Clin Invest. 2011 Sep;121(9):3375-83
references.pmid: 21881215
references.citation: Lancet. 2008 May 17;371(9625):1665-74
references.pmid: 18486739
references.citation: Annu Rev Biochem. 1995;64:621-51
references.pmid: 7574495
references.citation: Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7307-11
references.pmid: 7638186
references.citation: J Biol Chem. 1997 Feb 28;272(9):6073-7
references.pmid: 9038232
references.citation: Gastroenterology. 2008 Oct;135(4):1130-41
references.pmid: 18706417
references.citation: Org Lett. 2009 May 7;11(9):1999-2002
references.pmid: 19385672
references.citation: N Engl J Med. 2007 Feb 8;356(6):580-92
references.pmid: 17287478
references.citation: Nat Rev Immunol. 2008 Jul;8(7):559-68
references.pmid: 18575461
references.citation: Curr Opin Pharmacol. 2006 Aug;6(4):379-86
references.pmid: 16713356
references.citation: Proteins. 2011 Feb;79(2):393-401
references.pmid: 21117080
references.citation: J Immunol. 2013 Mar 1;190(5):2335-44
references.pmid: 23359498
references.citation: J Biol Chem. 1996 Apr 19;271(16):9503-9
references.pmid: 8621622
references.citation: EMBO J. 1995 Apr 3;14(7):1421-9
references.pmid: 7537214
references.citation: J Biol Chem. 2002 Sep 13;277(37):33676-82
references.pmid: 12087100
references.citation: J Biol Chem. 1999 Nov 5;274(45):32507-11
references.pmid: 10542297
references.citation: J Clin Invest. 2006 May;116(5):1310-6
references.pmid: 16670770
references.citation: Nature. 1993 Nov 11;366(6451):129-35
references.pmid: 8232552
references.citation: Annu Rev Immunol. 2008;26:677-704
references.pmid: 18173375
references.citation: Cell. 1993 Jul 30;74(2):227-36
references.pmid: 8343951
references.citation: J Exp Med. 1995 May 1;181(5):1755-62
references.pmid: 7722452
references.citation: Chem Biol. 2005 Jun;12(6):621-37
references.pmid: 15975507
references.citation: Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8686-91
references.pmid: 15937121
references.citation: Annu Rev Immunol. 2004;22:929-79
references.pmid: 15032600
references.citation: Nature. 2008 Jul 17;454(7202):350-2
references.pmid: 18469800
references.citation: J Biol Chem. 1999 Jan 22;274(4):1891-7
references.pmid: 9890942
references.citation: Immunity. 2000 Oct;13(4):561-71
references.pmid: 11070174
references.citation: Trends Mol Med. 2008 Mar;14(3):109-19
references.pmid: 18261959
references.citation: Immunity. 2012 Apr 20;36(4):515-28
references.pmid: 22520845
references.citation: J Exp Med. 2011 Feb 14;208(2):235-49
references.pmid: 21300911
references.citation: Nature. 1996 Jul 11;382(6587):174-7
references.pmid: 8700209
references.citation: Lancet. 2008 May 17;371(9625):1675-84
references.pmid: 18486740
references.citation: J Biol Chem. 2001 Jan 26;276(4):2725-32
references.pmid: 11035029
references.citation: J Biol Chem. 2003 Jan 17;278(3):1910-4
references.pmid: 12417590
references.citation: Immunity. 2000 Oct;13(4):549-60
references.pmid: 11070173
references.citation: J Biol Chem. 1996 Aug 9;271(32):19483-8
references.pmid: 8702638
references.citation: Nature. 1993 Dec 9;366(6455):580-3
references.pmid: 7504784
references.citation: J Exp Med. 2006 Oct 30;203(11):2473-83
references.pmid: 17030949
references.citation: PLoS One. 2012;7(6):e39141
references.pmid: 22723949
references.citation: Dermatol Ther. 2010 Mar-Apr;23(2):101-13
references.pmid: 20415816
references.citation: J Pediatr. 2012 Jun;160(6):1055-7
references.pmid: 22402565
references.citation: J Immunol. 2002 Jun 1;168(11):5699-708
references.pmid: 12023369
references.citation: Annu Rev Immunol. 2011;29:71-109
references.pmid: 21166540
references.citation: J Biol Chem. 2000 Oct 6;275(40):31335-9
references.pmid: 10875937
references.citation: Annu Rev Med. 2009;60:97-110
references.pmid: 18976050
references.citation: Front Biosci (Landmark Ed). 2011 Jun 01;16:3214-32
references.pmid: 21622231
references.citation: Gut. 2007 Oct;56(10):1333-6
references.pmid: 17872562
references.citation: Science. 1994 Jun 24;264(5167):1918-21
references.pmid: 8009221
references.citation: Immunity. 2012 Apr 20;36(4):542-50
references.pmid: 22520847
references.citation: Immunity. 2006 Nov;25(5):745-55
references.pmid: 17088085
references.citation: EMBO J. 2003 Feb 3;22(3):537-47
references.pmid: 12554654
references.citation: Am J Gastroenterol. 2009 Nov;104(11):2768-73
references.pmid: 19672253
references.citation: Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11594-9
references.pmid: 14500783
references.citation: Nature. 1993 Dec 9;366(6455):583-5
references.pmid: 7504785
references.citation: Nat Immunol. 2011 May;12(5):383-90
references.pmid: 21502992
references.citation: Cell. 1992 Jul 24;70(2):313-22
references.pmid: 1386289
references.citation: J Exp Med. 2004 Jan 5;199(1):125-30
references.pmid: 14707118
references.citation: J Exp Med. 1995 Jan 1;181(1):399-404
references.pmid: 7528775
references.citation: J Immunol. 2009 May 1;182(9):5836-45
references.pmid: 19380832