A Novel Histone Deacetylase 6 Inhibitor, CKD-H059 Inhibits the Inflammatory Response in Rheumatoid Arthritis

Yu Jin Jang¹, Bo Ram Oh², Hyojin Lim³, Daekwon Bae³, Nina Ha³, Young il Choi⁴, Jin Kyun Park⁵, Eun Young Lee⁵, Eun Bong Lee⁵ and Yeong Wook Song^5,6, ¹Department of Molecular Medicine and Biopharmaceutical Sciences, BK 21 plus Graduate School of Convergence Science and Technology, and College of Medicine or College of Parmarcy, Seoul National University, Seoul, South Korea, ²Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine, Seoul National University, Seoul, South Korea, ³Department of Pharmacology and Toxicology, CKD Research Institute, CKD Pharmaceutical Company, Seoul, South Korea, ⁴315-20 dongbaekjukjeon-daero, giheung-gu, Pharmacology lab, Hyo-Jong Research Laboratories, CKD Pharmaceutical Company, Yongin-si, South Korea, ⁵Division of Rheumatology, Department of Internal Medicine, Seoul National University, Seoul, South Korea, ⁶Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine Seoul National University, Seoul, South Korea

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: histone acetylation, regulatory cells and rheumatoid arthritis (RA)

Session Information

Date: Monday, November 9, 2015

Title: Rheumatoid Arthritis - Human Etiology and Pathogenesis Poster II

Session Type: ACR Poster Session B

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

Background/Purpose: Epigenetic changes including histone modification play an important role in development of rheumatoid arthritis (RA). Histone deacetylase inhibitor (HDACi) increases transcription of numerous genes by rendering chromatin state more accessible for transcription factor and RNA-polymerase, leading to anti-proliferative and anti-inflammatory effects. In addition, direct change in acetylation state of cellular proteins may alter cellular function.

This study was aimed to investigate the effects of CKD-H059, a novel HDAC-6 inhibitor, on regulatory T (Treg) cells and fibroblast-like-synoviocytes (FLS) of RA patients in vitro and on development of arthritis in vivo.

Methods: Regulatory T cells (iTreg) were induced from naïve CD4+ T cells of RA patients. CSFE labeled effector T cells (Teff) from healthy subjects were co-cultured with iTreg in the increasing concentrations of CKD-H059 and Teff proliferation was analyzed by flow cytometry. After 24 hour activation with IL-1β in the increasing concentrations of CKD-H059, proliferation and IL-6 production of RA-FLS were assessed. Cytoplasmic acetylation of α-tubulin in the activated RA-FLS was visualized by confocal microscopy. Adjuvant-induced arthritis (AIA) was induced in mice that were treated with oral CKD-H059 (3, 10, 30, 50, 100 mg/kg) and the severity of arthritis was assessed on 9, 13, and 16 days.

Results: In the presence of CKD-H059, iTreg efficiently inhibited the proliferation of Teff in a dose dependent manner. CKD-H059 induced acetylation of α-tubulin in cytoskeleton with subsequent cell morphology change (i.e. from long spindle form into round flat cells) and inhibited cell proliferation and production of pro-inflammatory cytokine IL-6. In AIA mice, oral CKD-H059 was able to prevent the development of clinical arthritis in a dose-dependent manner.

Conclusion: The novel HDAC6 inhibitor CKD-H059 inhibits the inflammatory response in T cells and FLS of RA in vitro and ameliorates arthritis severity in vivo. Therefore, CKD-H059 might offer a novel treatment option for RA.

Disclosure: Y. J. Jang, None; B. R. Oh, None; H. Lim, None; D. Bae, None; N. Ha, None; Y. I. Choi, None; J. K. Park, None; E. Y. Lee, None; E. B. Lee, None; Y. W. Song, None.

To cite this abstract in AMA style:

Jang YJ, Oh BR, Lim H, Bae D, Ha N, Choi YI, Park JK, Lee EY, Lee EB, Song YW. A Novel Histone Deacetylase 6 Inhibitor, CKD-H059 Inhibits the Inflammatory Response in Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/a-novel-histone-deacetylase-6-inhibitor-ckd-h059-inhibits-the-inflammatory-response-in-rheumatoid-arthritis/. Accessed .

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