HDAC6 inhibitors(Taipei Medical University)

Histone deacetylase 6 (HDAC6) is a crucial therapeutic target for a variety of diseases, including inflammation, autoimmune disorders, neurodegenerative diseases, cancer, viral infections, and drug addiction. Therefore, the discovery of selective HDAC6 inhibitors is essential for clinical application. In this study, we designed and synthesized a novel series of quinazolin-4-one-based selective HDAC6 inhibitors. Among them, the most potent compound, 5b (IC₅₀, 17.15 nM, HDAC6) exhibited 19-fold selectivity over HDAC1 and demonstrated significant anti-proliferative activity, with a GI₅₀ value of 2.4 μM against the MCF-7/ADR cell line. Additionally, compound 5b effectively induced the acetylation of α-tubulin, without affecting histone H3 acetylation in MCF-7/ADR cells, confirming its selectivity toward HDAC6. Compound 5b effectively suppressed cell proliferation by inducing apoptosis, as evidenced by colony formation assays and FACS analysis. Molecular docking study revealed that compound 5b effectively occupied the active site of HDAC6, supporting its strong binding affinity and selectivity. In vitro liver microsomal stability studies revealed that compound 5b was stable in both human and mouse liver microsomes. Furthermore, in an HCT116 xenograft mouse model, compound 5b significantly inhibited tumor growth without affecting body weight. The combination of in vitro and in vivo studies provides robust evidence supporting the potential of compound 5b as a highly potent and selective HDAC6 inhibitor, possessing promising anti-proliferative and apoptosis-inducing properties for further preclinical development.

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by a progressive fibrotic phenotype. Immunohistochemical studies on HDAC6 overexpression in IPF lung tissues confirmed that IPF is associated with aberrant HDAC6 activity. We herein developed a series of novel HDAC6 inhibitors that can be used as potential pharmacological tools for IPF treatment. The best-performing derivative H10 showed good selectivity for multiple isoforms of the HDAC family. The structural analysis and structure-activity relationship studies of H10 will contribute to optimizing the binding mode of the new molecules. The pharmacological mechanism of H10 to inhibit pulmonary fibrosis was validated, and its ability to inhibit the IPF phenotype was also demonstrated. Moreover, H10 showed satisfactory metabolic stability. The efficacy of H10 was also determined in a mouse model of bleomycin-induced pulmonary fibrosis. The results highlighted in this paper may provide a reference for the identification of new drug molecules for the treatment of IPF.