CKD-506: A novel HDAC6-selective inhibitor that exerts therapeutic effects in a rodent model of multiple sclerosis

Abstract

Despite advances in therapeutic strategies for multiple sclerosis (MS), the therapy options remain limited with various adverse effects. Here, the therapeutic potential of CKD-506, a novel HDAC6-selective inhibitor, against MS was evaluated in mice with myelin oligodendrocyte glycoprotein35–55 (MOG35–55)-induced experimental autoimmune encephalitis (EAE) under various treatment regimens. CKD-506 exerted prophylactic and therapeutic effects by regulating peripheral immune responses and maintaining blood–brain barrier (BBB) integrity. In MOG35–55-re-stimulated splenocytes, CKD-506 decreased proliferation and downregulated the expression of IFN-γ and IL-17A. CKD-506 downregulated the levels of pro-inflammatory cytokines in the blood of EAE mice. Additionally, CKD-506 decreased the leakage of intravenously administered Evans blue into the spinal cord; CD4+ T cells and CD4−CD11b+CD45+ macrophage/microglia in the spinal cord was also decreased. Moreover, CKD-506 exhibited therapeutic efficacy against MS, even when drug administration was discontinued from day 15 post-EAE induction. Disease exacerbation was not observed when fingolimod was changed to CKD-506 from day 15 post-EAE induction. CKD-506 alleviated depression-like behavior at the pre-symptomatic stage of EAE. In conclusion, CKD-506 exerts therapeutic effects by regulating T cell- and macrophage-mediated peripheral immune responses and strengthening BBB integrity. Our results suggest that CKD-506 is a potential therapeutic agent for MS.

Tc17 cells in autoimmune diseases

“…[ 99 ] Falcon et al [ 100 ] showed that Diazepam (DZ) treatment inhibited allogeneic Th1 and Th17 responses in vitro by preventing lipopolysaccharide-induced DC ability, and also that DZ reduced the release of IFN-γ and IL-17 by splenocytes from untreated sick mice in vitro. Bae et al [ 101 ] showed that CKD-506, a novel HDAC6-selective inhibitor, downregulated the expression of IFN-γ and IL-17A in MOG 35-55 -re-stimulated splenocytes, and also reduced the levels of pro-inflammatory cytokines in the blood of EAE mice.…”

Role of Selective Histone Deacetylase 6 Inhibitor ACY-1215 in Cancer and Other Human Diseases

“…However, except for ACY-1215, the present application range of other HDAC6 inhibitors is limited. Studies on ACY-241 ( Ray et al, 2018 ; Cosenza et al, 2020 ; Awad et al, 2021 ; Park et al, 2021 ) and KA2507 ( Tsimberidou et al, 2021 ) mainly focused on tumors, CKD-504 ( Choi et al, 2020 ; Ha et al, 2020 ; Jeong et al, 2022 ; Smith et al, 2022 ) focused on neurological diseases, and CKD-506 ( Choi et al, 2018 ; Park et al, 2020 ; Bae et al, 2021 ) focused on inflammatory diseases. Although ACY-241 and KA2507 show higher selectivity over ACY-1215 on HDAC6, its studies on other diseases needs further research ( Table 3 ).…”

The Immunomodulatory Potential of Short-Chain Fatty Acids in Multiple Sclerosis

“…HDAC inhibitors (HDAC-i) have been extensively studied for their potential in suppressing malignant cells, particularly in the context of glioblastoma [ 75 , 76 ]. Bae et al, in a murine experimental autoimmune encephalomyelitis (EAE) model, demonstrated that CDK-506, an HDAC6-i decreased T cell and macrophage passage in the spinal cord, reduced Th1 cell-related cytokines and improved the BBB integrity by upregulating occludin expression [ 77 ]. It also indirectly up-regulated Th2-dependent immune responses.…”