Background/Purpose: Autoimmune disease such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) is a chronic inflammatory disorder, significantly limiting quality of life. Even though the dramatic improvement with the new therapeutics had appeared over the past dedicates, there is still huge unmet medical needs. Recently, it was reported that epigenetic regulation is deeply involved in the development of autoimmune disease and that the inhibition of histone deacetylase showed significant immunomodulation. Herein, we introduce highly potent and selective histone deacetylase 6 inhibitor CKD-506 as a novel therapeutic drug for RA and IBD.

Methods: The inhibitory activity and selectivity of CKD-506 for HDAC6 were determined by enzyme assay. The acetylation of tubulin in PBMCs by CKD-506 was determined by western blot. The in vivo efficacy of CKD-506 in RA or IBD was evaluated in adjuvant (AIA)- and collagen (CIA)-induced arthritis or DSS- and CD4⁺CD45RB^hi T cell adaptive transfer-induced colitis animal model respectively. To test the effect of CKD-506 on T cell function, CFSE-labeled effector T cells (T_eff) from mouse splenocytes were co-cultured with T_reg in the presence of CKD-506 and T_eff proliferation was analyzed by flow cytometry. The ex vivo anti-inflammatory effect of CKD-506 was tested with peripheral mononuclear cells (PBMCs) or synoviocytes from RA patients. The effect of CKD-506 on inflammatory mediators in T cell adaptive transfer colitis was screened by real time RT-PCR.

Results: CKD-506 was had a potent and selective inhibitory activity on HDAC6 with an IC50 of 5 nM. CKD-506 highly induced acetylation of tubulin a substrate for HDAC6 in human PBMCs and lymphoid tissue collected from normal rat. In the arthritis animal models, CKD-506 inhibited severity of arthritis in a dose dependent manner and showed strong synergistic efficacy with methotrexate combination. The proliferation of T_eff was suppressed by CKD-506. Interestingly, the CKD-506 significantly inhibited TNF a but induced IL-10 production in PBMCs. CKD-506 inhibited IL-1b induced CCL-2, CXCL-8, CXCL-10 production in fibroblast-like synoviocytes from RA patients. In IBD animal models, CKD-506 significantly repressed disease progression and highly inhibited the expression of inflammatory mediators in colon tissues of T cell adaptive transferred colitis animal. (Current status: Phase I in EU, EudraCT number: 2016-002816-42)

Conclusion: The novel HDAC6 inhibitor, CKD-506 had a therapeutic potential in autoimmune disease such as RA and IBD through the inhibition of inflammatory mediators and the regulation of T cell functions.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/ckd-506-a-novel-inhibitor-of-histone-deacetylase-6-hdac6-has-a-therapeutic-potential-in-rheumatoid-arthritis-and-inflammatory-bowel-disease/