Histone deacetylase 6 (HDAC6) induces the expression of pro-inflammatory cytokines in macrophages; therefore, HDAC inhibitors may be beneficial for the treatment of macrophage-associated immune disorders and chronic inflammatory diseases, including atherosclerosis and rheumatoid arthritis. Structure-activity relationship studies were conducted on various phenyl hydroxamate HDAC6 inhibitors with indolone/indazolone-based bi- or tricyclic ring moieties as the cap group aiming to develop novel anti-arthritic drug candidates. Several compounds exhibited nanomolar activity and HDAC6 selectivity greater than 500-fold over HDAC1. Compound 21, a derivative with the tetrahydroindazolone cap group, is a potent HDAC6 inhibitor with an IC50 of 18 nM and 217-fold selectivity over HDAC1 and showed favorable oral bioavailability in animals. Compound 21 increases the acetylation level of tubulin without affecting histone acetylation in cutaneous T-cell lymphoma cells and inhibits TNF-α secretion in LPS-stimulated macrophage cells. The anti-arthritic effects of compound 21 were evaluated using a rat adjuvant-induced arthritis (AIA) model. Treatment with compound 21 significantly reduced the arthritis score, and combination treatment with methotrexate showed a synergistic effect in AIA models. We identified a novel HDAC6 inhibitor, compound 21, with excellent in vivo anti-arthritic efficacy, which can lead to the development of oral anti-arthritic drugs.

Background Diabetic retinopathy (DR), a major blindness cause in developed countries, is intricately linked to diabetes management and its duration. Here, we demonstrate that HDAC6 mediates NLRP3 inflammasome activation under diabetic conditions, leading to retinal inflammation and degeneration. Methods This study demonstrated the therapeutic effects of HDAC6 genetic ablation, pharmacological inhibition, and HDAC6-deficient bone marrow transplantation in a diabetes model induced by streptozotocin and a high-fat diet. The therapeutic potential was evaluated from a metabolic perspective, including ocular pathologies such as retinal lesions, neovascularization, and vascular leakage. Results We discovered that inhibition or genetic ablation of HDAC6 markedly alleviates DR symptoms by dampening NLRP3 inflammasome activation and mitigating retinal damage. Moreover, bone marrow transplantation from HDAC6-deficient mice into wild-type counterparts reversed DR symptoms, underscoring the significance of HDAC6 in systemic immune regulation. The study introduces a novel HDAC6 inhibitor, noted for superior bioavailability and blood-retinal barrier permeability, further highlights the therapeutic promise of targeting HDAC6 in DR. Conclusions Our findings not only underscore the crucial role of HDAC6 in the immune regulatory mechanisms underlying DR pathogenesis through NLRP3 inflammasome activation but also position HDAC6 inhibition as a promising strategy for addressing diabetic complications beyond DR.

Histone deacetylase (HDAC) inhibitors have been recognized as promising approaches to the treatment of various human diseases including cancer, inflammation, neurodegenerative diseases, and metabolic disorders. Several pan-HDAC inhibitors are currently approved only as anticancer drugs. Interestingly, SAHA (vorinostat), one of clinically available pan-HDAC inhibitors, shows an anti-inflammatory effect at concentrations lower than those required for inhibition of tumor cell growth. It was also reported that HDAC6 selective inhibitor tubastatin A has anti-inflammatory and anti-rheumatic effect. In our efforts to develop novel HDAC inhibitors, we rationally designed various HDAC inhibitors based on the structures of two hit compounds identified by virtual screening of chemical database. Among them, 9a ((E)-N-hydroxy-4-(2-styrylthiazol-4-yl)butanamide) was identified as a HDAC6 selective inhibitor (IC50 values of 0.199 μM for HDAC6 versus 13.8 μM for HDAC1), and it did not show significant cytotoxicity against HeLa cells. In vivo biological evaluation of 9a was conducted on a lipopolysaccharide (LPS)-induced mouse model of sepsis. The compound 9a significantly improved 40% survival rate (P = 0.0483), and suppressed the LPS-induced increase of TNF-α and IL-6 mRNA expression in the liver of mice. Our study identified novel HDAC6 selective inhibitor 9a, which may serve as a potential lead for the development of anti-inflammatory or anti-sepsis agents.