Open Access Highly Accessed Research article

Selective inhibition of spleen tyrosine kinase (SYK) with a novel orally bioavailable small molecule inhibitor, RO9021, impinges on various innate and adaptive immune responses: implications for SYK inhibitors in autoimmune disease therapy

Cheng Liao15*, Jonathan Hsu16, Yong Kim1, Dong-Qing Hu1, Daigen Xu15, Jun Zhang1, Achal Pashine1, John Menke1, Toni Whittard1, Natasha Romero2, Theresa Truitt2, Michelle Slade2, Christine Lukacs2, Johannes Hermann3, Mingyan Zhou4, Matthew Lucas37, Satwant Narula1, Julie DeMartino15 and Seng-Lai Tan15

Author Affiliations

1 Inflammation Discovery and Therapeutic Area, Hoffmann-La Roche, 340 Kingsland Street, Nutley, NJ 07110, USA

2 Discovery Technology, Hoffmann-La Roche, 340 Kingsland Street, Nutley, NJ 07110, USA

3 Discovery Chemistry, Hoffmann-La Roche, 340 Kingsland Street, Nutley, NJ 07110, USA

4 Drug Metabolism and Pharmacokinetics, Hoffmann-La Roche, 340 Kingsland Street, Nutley, NJ 07110, USA

5 Present address: EMD Serono Research & Development Institute, 45A Middlesex Turnpike, Billerica, MA 01821, USA

6 Present address: Lilly Research Laboratories, Tailored Therapeutics Autoimmunity/Muscular and Skeletal, Indianapolis, IN 46285, USA

7 Present address: Cubist Pharmaceuticals, 65 Hayden Avenue, Lexington, MA 02421, USA

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Arthritis Research & Therapy 2013, 15:R146  doi:10.1186/ar4329

Published: 4 October 2013

Abstract

Introduction

Spleen tyrosine kinase (SYK) is a key integrator of intracellular signals triggered by activated immunoreceptors, including Bcell receptors (BCR) and Fc receptors, which are important for the development and function of lymphoid cells. Given the clinical efficacy of Bcell depletion in the treatment of rheumatoid arthritis and multiple sclerosis, pharmacological modulation of Bcells using orally active small molecules that selectively target SYK presents an attractive alternative therapeutic strategy.

Methods

A SYK inhibitor was developed and assayed in various in vitro systems and in the mouse model of collagen-induced arthritis (mCIA).

Results

A novel ATP-competitive inhibitor of SYK, 6-[(1R,2S)-2-Amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide, designated RO9021, with an adequate kinase selectivity profile and oral bioavailability, was developed. In addition to suppression of BCR signaling in human peripheral blood mononuclear cells (PBMC) and whole blood, FcγR signaling in human monocytes, and FcϵR signaling in human mast cells, RO9021 blocked osteoclastogenesis from mouse bone marrow macrophages in vitro. Interestingly, Toll-like Receptor (TLR) 9 signaling in human Bcells was inhibited by RO9021, resulting in decreased levels of plasmablasts, immunoglobulin (Ig) M and IgG upon B-cell differentiation. RO9021 also potently inhibited type I interferon production by human plasmacytoid dendritic cells (pDC) upon TLR9 activation. This effect is specific to TLR9 as RO9021 did not inhibit TLR4- or JAK-STAT-mediated signaling. Finally, oral administration of RO9021 inhibited arthritis progression in the mCIA model, with observable pharmacokinetics (PK)-pharmacodynamic (PD) correlation.

Conclusions

Inhibition of SYK kinase activity impinges on various innate and adaptive immune responses. RO9021 could serve as a starting point for the development of selective SYK inhibitors for the treatment of inflammation-related and autoimmune-related disorders.