Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis.
Bruton's tyrosine kinase (Btk) is a therapeutic target for rheumatoid arthritis, but the cellular and molecular mechanisms by which Btk mediates inflammation are poorly understood. Here we describe the discovery of CGI1746, a small-molecule Btk inhibitor chemotype with a new binding mode that stabilizes an inactive nonphosphorylated enzyme conformation. CGI1746 has exquisite selectivity for Btk and inhibits both auto- and transphosphorylation steps necessary for enzyme activation. Using CGI1746, we demonstrate that Btk regulates inflammatory arthritis by two distinct mechanisms. CGI1746 blocks B cell receptor-dependent B cell proliferation and in prophylactic regimens reduces autoantibody levels in collagen-induced arthritis. In macrophages, Btk inhibition abolishes FcγRIII-induced TNFα, IL-1β and IL-6 production. Accordingly, in myeloid- and FcγR-dependent autoantibody-induced arthritis, CGI1746 decreases cytokine levels within joints and ameliorates disease. These results provide new understanding of the function of Btk in both B cell- or myeloid cell-driven disease processes and provide a compelling rationale for targeting Btk in rheumatoid arthritis.
Department of Discovery Biology, CGI Pharmaceuticals, Branford, Connecticut, USA.
Julie A
JA
Di Paolo
Tao
T
Huang
Mercedesz
M
Balazs
James
J
Barbosa
Kai H
KH
Barck
Brandon J
BJ
Bravo
Richard A D
RA
Carano
James
J
Darrow
Douglas R
DR
Davies
Laura E
LE
DeForge
Lauri
L
Diehl
Ronald
R
Ferrando
Steven L
SL
Gallion
Anthony M
AM
Giannetti
Peter
P
Gribling
Vincent
V
Hurez
Sarah G
SG
Hymowitz
Randall
R
Jones
Jeffrey E
JE
Kropf
Wyne P
WP
Lee
Patricia M
PM
Maciejewski
Scott A
SA
Mitchell
Hong
H
Rong
Bart L
BL
Staker
J Andrew
JA
Whitney
Sherry
S
Yeh
Wendy B
WB
Young
Christine
C
Yu
Juan
J
Zhang
Karin
K
Reif
Kevin S
KS
Currie
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D001323:Autoantibodies; D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; C555057:CGI 1746; D053583:Interleukin-1beta; D015850:Interleukin-6; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse