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Abstract Number: 2000

Anti-inflammatory Effect of Novel Spleen Tyrosine Kinase Inhibitor, SKI-O-592, on Fibroblast-like Synoviocyte in Rheumatoid Arthritis and THP-1 Cell

Seon Uk Kim1, Hyun Jung Yoo 2, Shin Eui Kang 3, Ji soo Park 4, Ra Ham Kim 5, Jung-Ho Kim 6, Hae-Jun Hwang 6, Jin Kyun Park 7, Eun Young Lee 7 and Yeong-Wook Song 8, 1Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine, Seoul National University, Seoul, Republic of Korea, 2Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine, Seoul National University, Seoul, Repulbic of Korea, Seoul, Republic of Korea, 3Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine, Seoul National University, Seoul, Republic of Korea, Seoul, Republic of Korea, 4Division of Rheumatology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea., Seoul, Republic of Korea, 5Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine, Seoul National University, Seoul, Republic of Korea, Seoul, Republic of Korea, 6Oscotec Inc., Seongnam, Republic of Korea, 7Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea, seoul, Republic of Korea, 8Seoul National University Hospital, Seoul, Republic of Korea

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: rheumatoid arthritis (RA) and tyrosine kinase inhibition

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Session Information

Date: Tuesday, November 12, 2019

Title: RA – Etiology & Pathogenesis Poster II

Session Type: Poster Session (Tuesday)

Session Time: 9:00AM-11:00AM

Background/Purpose: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by bone and cartilage destruction with leukocyte infiltration and activation at synovial tissue. The fibroblast-like synoviocytes (FLS) have a central role in disease pathogenesis and in vitro FLS invasiveness which correlates with articular damage in RA patients. Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase known to have a crucial role in immune receptor signaling. Recently, a number of studies have revealed that aberrant SYK activation is associated with diverse allergic disorders and antibody-mediated autoimmune diseases such as rheumatoid arthritis, asthma and allergic rhinitis. A novel small-molecule SYK inhibitor, SKI-O-592, was designed and synthesized. The aim of this study is to evaluate the inhibitory effect of SYK inhibitor on inflammation and migration in RA FLS and THP-1 cell.

Methods: Selectivity of SKI-O-592 was evaluated by KinaseProfiler platform consisting of 293 human purified kinases using ATP Km for each kinase. A series of concentrations of ATP ranged from 10 to 1,500 µM were simultaneously incubated with cell-free kinase reaction. FLS were isolated from synovial tissues of RA patients, and treated with SKI-O-592 under tumor necrosis factor alpha (TNF-α). FLS were stimulated with TNF-α for 48 hr after 1 hr treatment of SKI-O-592. After stimulation, cell viability were measured using CCK-8 assay. The levels of IL-6, CXCL10, MMP-3 and TNF-α were measured in culture supernatant of RA FLS and THP-1 cell by ELISA. Wound healing assay were performed to evaluate cell migration ability. The expression of α-tubulin, phosphorylated SYK and phosphoinositide 3-kinase (PI3K) were determined by Western blotting.

Results: SKI-O-592 inhibited the activity of recombinant human SYK enzymes with an IC50 of 5.1 nM. The kinases with more than 75% inhibition by 0.1 μM SKI-O-592 were SYK, YES and ROCK-II. The number of migrated cell to wound region was decreased in SKI-O-592 treated RA FLS without the change in cell viability. SKI-O-592 reduced the levels of cytokine and chemokine secretion including IL-6, CXCL10 and MMP-3 in RA FLS. Secreted TNF-α levels were decreased in THP-1 cell by SKI-O-592. Phosphorylation of PI3K was decreased after 30min of SKI-O-592 treatment. The viability and proliferation of the cells were not affected.

Conclusion: The novel SYK inhibitor, SKI-O-592 decreased the production of pro-inflammatory cytokine, chemokine and metalloproteinase in RA FLS. SKI-O-592 decreased the phosphorylation of PI3K. SKI-O-592 may provide a new therapeutic strategy in RA patients.


Disclosure: S. Kim, None; H. Yoo, None; S. Kang, None; J. Park, None; R. Kim, None; J. Kim, None; H. Hwang, None; J. Park, None; E. Lee, None; Y. Song, Astellas Pharma, Inc., 9.

To cite this abstract in AMA style:

Kim S, Yoo H, Kang S, Park J, Kim R, Kim J, Hwang H, Park J, Lee E, Song Y. Anti-inflammatory Effect of Novel Spleen Tyrosine Kinase Inhibitor, SKI-O-592, on Fibroblast-like Synoviocyte in Rheumatoid Arthritis and THP-1 Cell [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/anti-inflammatory-effect-of-novel-spleen-tyrosine-kinase-inhibitor-ski-o-592-on-fibroblast-like-synoviocyte-in-rheumatoid-arthritis-and-thp-1-cell/. Accessed .
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