CKD-506, First-in-Class Histone Deacetylase (HDAC) 6 Inhibitor, Ameliorates Rheumatoid Arthritis through Regulation of Inflammation and T Cell Function

Jieun Shin¹, Nina Ha¹, Daekwon Bae¹, Dong-Hyeon Suh¹, Ji-yeon Baek¹, Jae Hyun Jun¹, Yong Jae Lee¹, Changsik Lee¹, Sei-Hwan Kim¹, Young Il Choi¹, Keun Ho Ryu¹, Yu Jin Jang², Sehui Shon², Yeong Wook Song³, Gi Soo Youn⁴ and Jinseu Park⁴, ¹Research Institute of Chong Kun Dang Pharmaceutical Corporation, Yongin, Korea, Republic of (South), ²Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul, Korea, Republic of (South), ³Seoul National University College of Medicine, Seoul, Korea, Republic of (South), ⁴Department of Biomedical Science, Hallym University, Chuncheon, Korea, Republic of (South)

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: Histone Modification and rheumatoid arthritis (RA)

Session Information

Date: Sunday, October 21, 2018

Title: Rheumatoid Arthritis – Animal Models Poster

Session Type: ACR Poster Session A

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

Background/Purpose: Broad-spectrum histone deacetylase inhibitors are well known for immunomodulatory functions. However, due to their toxicity, HDAC subtype specific inhibition has been proposed as therapeutic strategy for treatment of autoimmune diseases. Herein, we introduce CKD-506, a potent and selective HDAC6 inhibitor, as an immunomodulatory agent for treatment of rheumatoid arthritis.

Methods: The selectivity and potency of CKD-506 were determined by enzyme assay. Adjuvant- (AIA) induced arthritis animal model was used to evaluate its in vivo efficacy. Peripheral blood mononuclear cells (PBMCs) and fibroblast-like synoviocytes (FLS) from rheumatoid arthritis (RA) patients were used for ex vivo studies. Macrophage cells with HDAC6 overexpression were used for mechanism studies.

Results: CKD-506 showed potent and selective inhibitory activity on HDAC6 with an IC₅₀ of 5 nM in enzyme assay and induced tubulin acetylation in human PBMCs and rat lymphocytes. In AIA model, CKD-506 strongly inhibited arthritis score as well as serum anti-CCP level. Interestingly, CKD-506 exhibited strong synergistic efficacy with MTX in rat AIA model. In ex vivo study with RA patients’ samples, CKD-506 inhibited secretion of inflammatory cytokines and chemokines such as TNFa and CXCL10 but induced IL-10 secretion. Moreover, the induced regulatory T cells of RA patients, which had been differentiated in the presence of CKD-506, significantly inhibited the proliferation of effector T cells. In mechanism studies, HDAC6 overexpression induced the expression of various inflammation mediators such as cytokines, chemokines and adhesion molecules from macrophages but CKD-506 inhibited HDAC6-mediated inflammatory responses of macrophage in a dose dependent manner. CKD-506 with MTX exhibited better anti-inflammatory effect on macrophages with HDAC6 overexpression.

Conclusion: CKD-506 exhibited strong efficacy in ex vivo studies with RA patients’ samples as well as in vivo rat AIA model. CKD-506 is a first-in-class HDAC6 inhibitor for treatment of rheumatoid arthritis. (Current status: in preparation of Phase IIa for moderate to severe RA patients in EU).

Disclosure: J. Shin, None; N. Ha, None; D. Bae, None; D. H. Suh, None; J. Y. Baek, None; J. H. Jun, None; Y. J. Lee, None; C. Lee, None; S. H. Kim, None; Y. I. Choi, None; K. H. Ryu, None; Y. J. Jang, None; S. Shon, None; Y. W. Song, None; G. S. Youn, None; J. Park, None.

To cite this abstract in AMA style:

Shin J, Ha N, Bae D, Suh DH, Baek JY, Jun JH, Lee YJ, Lee C, Kim SH, Choi YI, Ryu KH, Jang YJ, Shon S, Song YW, Youn GS, Park J. CKD-506, First-in-Class Histone Deacetylase (HDAC) 6 Inhibitor, Ameliorates Rheumatoid Arthritis through Regulation of Inflammation and T Cell Function [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/ckd-506-first-in-class-histone-deacetylase-hdac-6-inhibitor-ameliorates-rheumatoid-arthritis-through-regulation-of-inflammation-and-t-cell-function/. Accessed .

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