M-134, a novel HDAC6-selective inhibitor, markedly improved arthritic severity in a rodent model of rheumatoid arthritis when combined with tofacitinib

Background: Although tofacitinib has shown highly significant efficacy for rheumatoid arthritis (RA), there are still a considerable number of patients that are non-responders owing to its limited effectiveness and various adverse effects. Thus, alternative options with better efficacy and lower toxicity are desired. Here, M-134, a recently developed HDAC6 inhibitor, was examined for its therapeutic potential when combined with tofacitinib in a rat model of RA. Methods: The single or combined administration of M-134 and tofacitinib was examined in complete Freund’s adjuvant-induced arthritis (AIA) or collagen-induced arthritis (CIA) rodent models. To evaluate the therapeutic and adverse effects, the following factors were observed: macroscopic or microscopic scoring of all four paws; the expression of ICAM-1, VCAM-1, and IP-10 in the joints and that of various cytokines and chemokines in the plasma; the weight of the thymus and the liver; and changes in hematological enzymes. Results: Combination treatment showed strong synergistic effects as measured by the clinical score and histological changes, without adverse effects such as weight loss in the thymus and increased liver enzymes (ALT and AST). Additionally, it also reduced ICAM-1, VCAM-1, and IP-10 expression in the joints, and M-134 increased the efficacy of tofacitinib by regulating various cytokines, such as interleukin (IL)-1β, IL-17, and TNF-α, in the serum of AIA rats. Differences in the cytokine expression for each drug were found in the CIA model. Conclusions: M-134 and tofacitinib combination therapy is a potential option for the treatment of RA through the regulation of cytokines, chemokines, and adhesion molecules

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

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 glycoprotein(35-55) (MOG(35-55))-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 MOG(35-55)-re-stimulated splenocytes, CKD-506 decreased proliferation and downregulated the expression of IFN-gamma 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