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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

Additional files

Additional file 1:

Figure S1 lists kinases with more than 90% binding efficiency with RO9021 (1 μM) in the KinomeScan assay. Figure S2 shows the X-ray crystal structure of SYK with front view (A) and top view (B), showing the ATP binding site with RO9021 bound. Black dashes, hydrogen bonds; orange dashes, hydrophobic contacts to the Gly454/Pro455 region. Figure S3 shows the pharmacokinetics profile of single oral dose of RO9021 in mouse.

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