Therapeutic potential of CKD-506, a novel selective histone deacetylase 6 inhibitor, in a murine model of rheumatoid arthritis

Abstract

Objectives Histone deacetylase (HDAC) 6 promotes inflammation. We investigated the anti-arthritic effects of CKD-506, a novel HDAC6 inhibitor, in vitro and in a murine model of arthritis as a novel treatment option for rheumatoid arthritis (RA). Methods HDAC6 was overexpressed in mouse peritoneal macrophages and RAW 264.7 cells and the effects of a HDAC6 inhibitor CKD-506 on cytokine production and activity of NF-κB and AP-1 signaling were examined. Peripheral blood mononuclear cells (PBMCs) from RA patients and fibroblast-like synoviocytes (FLS) were activated in the presence of CKD-506. Next, regulatory T cells (Treg) were induced from RA patients and co-cultured with healthy effector T cells (Teff) and cell proliferation was analyzed by flow cytometry. Finally, the effects of the inhibitor on the severity of arthritis was assessed in a murine model of adjuvant-induced arthritis (AIA). Results Overexpression of HDAC6 induced in macrophages to produce TNF-α and IL-6. The inhibitory effect of CKD-506 was mediated via blockade of NF-κB and AP-1 activation. HDAC6 inhibition reduced TNF-α and IL-6 production by activated RA-PBMCs. Also, CKD-506 inhibited production of MMP-1, MMP-3, IL-6 and IL-8 by activated FLS. In addition, CKD-506 inhibited proliferation of Teffs directly and indirectly by improving iTreg function. In AIA rats, oral CKD-506 improved clinical arthritis in a dose-dependent manner. A combination of sub-therapeutic CKD-506 and methotrexate exerted a synergistic effect. Conclusion The novel HDAC6 inhibitor CKD-506 induces regulatory immune responses in monocytes/macrophages, improves Treg function, and ameliorates arthritis severity in a murine model of RA. Thus, CKD-506 might be a novel and effective treatment option for RA.

Global research hotspots and frontier trends of epigenetic modifications in autoimmune diseases: a bibliometric analysis from 2012 to 2022

“…For instance, histone deacetylase 9 (HDAC9) has been found to play a crucial role in Treg cells, regulating their immunosuppressive function [30] . Inhibiting the expression of HDAC6 has been shown to improve Treg cell function [31] ,…”

Synthesis and structure‐activity relationship of thiol‐based histone deacetylase 6 inhibitors

“…KA-2507, in phase I, is used for patients with PD-L1 expressing solid tumors which have relapsed or are refractory to prior treatment (Zhang et al, 2021). Besides application in cancers, CKD-504 and CKD-506, both in phase I trials in South Korea, serve as a potential treatment for Huntington's disease and Autoimmune diseases, respectively (Park et al, 2020).…”