PBT-6, a Novel PI3KC2γ Inhibitor in Rheumatoid Arthritis
Juyoung Kim1,†, Kyung Hee Jung1,†, Jaeho Yoo2,†, Jung Hee Park1, Hong Hua Yan1, Zhenghuan Fang1, Joo Han Lim1, Seong-Ryul Kwon1, Myung Ku Kim1, Hyun-Ju Park2 and Soon-Sun Hong1,*
1Department of Medicine, College of Medicine, Inha University, Incheon 22313,
2School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
E-mail: hongs@inha.ac.kr
Tel: +82-32-890-3683, Fax: +82-32-890-2462
The first three authors contributed equally to this work.
Received: September 18, 2019; Revised: October 15, 2019; Accepted: October 17, 2019; Published online: November 18, 2019.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
Phosphoinositide 3-kinase (PI3K) is considered as a promising therapeutic target for rheumatoid arthritis (RA) because of its involvement in inflammatory processes. However, limited studies have reported the involvement of PI3KC2γ in RA, and the underlying mechanism remains largely unknown. Therefore, we investigated the role of PI3KC2γ as a novel therapeutic target for RA and the effect of its selective inhibitor, PBT-6. In this study, we observed that PI3KC2γ was markedly increased in the synovial fluid and tissue as well as the PBMCs of patients with RA. PBT-6, a novel PI3KC2γ inhibitor, decreased the cell growth of TNF-mediated synovial fibroblasts and LPS-mediated macrophages. Furthermore, PBT-6 inhibited the PI3KC2γ expression and PI3K/AKT signaling pathway in both synovial fibroblasts and macrophages. In addition, PBT-6 suppressed macrophage migration via CCL2 and osteoclastogenesis. In CIA mice, it significantly inhibited the progression and development of RA by decreasing arthritis scores and paw swelling. Three-dimensional micro-computed tomography confirmed that PBT-6 enhanced the joint structures in CIA mice. Taken together, our findings suggest that PI3KC2γ is a therapeutic target for RA, and PBT-6 could be developed as a novel PI3KC2γ inhibitor to target inflammatory diseases including RA.
Keywords: Rheumatoid arthritis, Collagen-induced arthritis, PI3KC2γ, RANKL


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