RT Journal Article
SR Electronic
T1 RN486 [6-Cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one], a Selective Bruton's Tyrosine Kinase (Btk) Inhibitor, Abrogates Immune Hypersensitivity Responses and Arthritis in Rodents
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.111.187740
DO 10.1124/jpet.111.187740
A1 Daigen Xu
A1 Yong Kim
A1 Jennifer Postelnek
A1 Minh Diem Vu
A1 Dong-Qing Hu
A1 Cheng Liao
A1 Mike Bradshaw
A1 Jonathan Hsu
A1 Jun Zhang
A1 Achal Pashine
A1 Dinesh Srinivasan
A1 Anita Levin
A1 John Woods
A1 Alison O'Mahony
A1 Timothy D Owens
A1 Yan Lou
A1 Ronald J Hill
A1 Satwant Narula
A1 Julie DeMartino
A1 Jay S Fine
YR 2012
UL http://jpet.aspetjournals.org/content/early/2012/01/06/jpet.111.187740.abstract
AB Genetic mutation and pharmacological inhibition of Bruton's tyrosine kinase (Btk) have both been shown to prevent the development of collagen-induced arthritis (CIA) in mice, providing a rationale for the development of Btk inhibitors for treating rheumatoid arthritis (RA). In the present study, we characterized a novel Btk inhibitor RN486 in vitro and in rodent models of immune hypersensitivity and arthritis. We demonstrated that RN486 not only potently and selectively inhibited the Btk enzyme, but also displayed functional activities in human cell-based assays in multiple cell types, blocking FcϵR crosslinking-induced degranulation in mast cells (IC50=2.9 nM), FcγR engagement-mediated TNFα production in monocytes (IC50=7.0 nM) and B cell receptor (BCR)-induced expression of an activation marker CD69 in B cells in whole blood (IC50=21.0 nM). RN486 displayed similar functional activities in rodent models, effectively preventing type I and type III hypersensitivity responses. More importantly, RN486 produced robust anti-inflammatory and bone protective effects in mouse CIA and rat adjuvant-induced arthritis (AIA) models. In the AIA model, RN486 inhibited both joint and systemic inflammation either alone or in combination with methotrexate, reducing both paw swelling and inflammatory markers in the blood. Together, our findings not only demonstrate that Btk plays an essential and conserved role in regulating immunoreceptor-mediated immune responses in both humans and rodents, but also provide evidence and mechanistic insights to support the development of selective Btk inhibitors as small molecule disease modifying drugs for RA and potentially other autoimmune diseases.