Discovery of novel selective HDAC6 inhibitors via a scaffold hopping approach for the treatment of idiopathic pulmonary fibrosis (IPF) in vitro and in vivo

Article

作者: Guo, Yuxi ; Ma, Enlong ; Xu, Yongnan ; Ma, Chao ; Qu, Wenhui ; Zhou, Xinru ; Quan, Jishun ; Zhao, Xianchen

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, and fatal pulmonary disease. Owing to its complex pathogenesis and lack of effective treatment, patients have a short survival time after diagnosis. Although pirfenidone and nintedanib can mitigate declines in lung function, neither has stopped the progression of IPF nor significantly improved long-term survival in patients. HDAC6 inhibitors have been reported to inhibit TGF-β1-induced collagen expression to protect mice from pulmonary fibrosis, and this pharmacological mechanism has been supported by immunohistochemical studies of HDAC6 overexpression in IPF lung tissue. In this study, a series of novel derivatives were obtained based on the reported active compounds through the ring closure strategy in scaffold hopping theory. Compound W28 was selected from in vitro screening for better HDAC6 selectivity, and it was used for in-depth pharmacokinetic and pharmacodynamic studies. Detailed molecular docking studies, molecular dynamics (MD) simulations and the structure-activity relationship (SAR) discussion will contribute to guiding the design of new molecules. In further studies, the ability of W28 to inhibit the IPF phenotype was confirmed, and the corresponding pharmacological mechanism was also demonstrated. Moreover, the pharmacokinetic characteristics of W28 were also tested to guide pharmacodynamic studies in vivo, and the therapeutic effect of W28 on bleomycin-induced pulmonary fibrosis in mice was found to be satisfactory. The results reported in this paper may provide a reference for promoting the discovery of new selective HDAC6 inhibitors as drug molecules for the treatment of IPF.

2024-09-01·Expert Opinion on Therapeutic Targets

Therapeutic indications for HDAC6 inhibitors in the peripheral and central nervous disorders

Review

作者: Rombouts, Frederik ; Prior, Robert ; Van Den Bosch, Ludo ; van Eyll, Jonathan ; Celanire, Sylvain

INTRODUCTIONInhibition of the enzymatic function of HDAC6 is currently being explored in clinical trials ranging from peripheral neuropathies to cancers. Advances in selective HDAC6 inhibitor discovery allowed studying highly efficacious brain penetrant and peripheral restrictive compounds for treating PNS and CNS indications.AREAS COVEREDThis review explores the multifactorial role of HDAC6 in cells, the common pathological hallmarks of PNS and CNS disorders, and how HDAC6 modulates these mechanisms. Pharmacological inhibition of HDAC6 and genetic knockout/knockdown studies as a therapeutic strategy in PNS and CNS indications were analyzed. Furthermore, we describe the recent developments in HDAC6 PET tracers and their utility in CNS indications. Finally, we explore the advancements and challenges with HDAC6 inhibitor compounds, such as hydroxamic acid, fluoromethyl oxadiazoles, HDAC6 degraders, and thiol-based inhibitors.EXPERT OPINIONBased on extensive preclinical evidence, pharmacological inhibition of HDAC6 is a promising approach for treating both PNS and CNS disorders, given its involvement in neurodegeneration and aging-related cellular processes. Despite the progress in the development of selective HDAC6 inhibitors, safety concerns remain regarding their chronic administration in PNS and CNS indications, and the development of novel compound classes and modalities inhibiting HDAC6 function offer a way to mitigate some of these safety concerns.

2023-02-01·Bioorganic & Medicinal Chemistry

Synthesis and biological evaluation of novel N-benzyltriazolyl-hydroxamate derivatives as selective histone deacetylase 6 inhibitors

Article

作者: Park, Gi Min ; Boggu, Pulla Reddy ; Jung, Young Hoon ; Nam, Gibeom ; Park, Hyun-Ju ; Kang, Ji Eun ; Kong, Sun Ju

Histone deacetylases (HDAC) regulate post-translational acetylation and the inhibition of these enzymes has emerged as an intriguing disease therapeutic. Among them, class IIb HDAC6 has the unique characteristic of mainly deacetylating cytoplasmic proteins, suggesting clinical applications for neurodegenerative diseases, inflammation, and cancer. In this study, we designed a novel N-benzyltriazolyl-hydroxamate scaffold based on the known HDAC6 inhibitors nexturastat A and tubastatin A. Among the 27 derivatives, 3-fluoro-4-((3-(2-fluorophenyl)-1H-1,2,4-triazol-1-yl)methyl)-N-hydroxybenzamide 4u (HDAC6 IC₅₀ = 7.08 nM) showed nanomolar HDAC6 inhibitory activity with 42-fold selectivity over HDAC1. Structure-activity relationship (SAR) and computational docking studies were conducted to optimize the triazole capping group. Docking analysis revealed that the capping group aligned with the conserved L1 pocket of HDAC6 and was associated with subtype selectivity. Overall, our study explored the triazole-based biaryl capping group and its substitution and orientation, suggesting a rationale for the design of HDAC6-selective inhibitors.

100 项与 HDAC6 inhibitors(Taipei Medical University) 相关的药物交易

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