Histone deacetylase 6 inhibitors in Alzheimer's disease therapy: structure design and challenges

Baiyun Dang; Hou Chen; Shiru Liu; Haijuan Liu; Zhiwen Kang; Zhen Yang; Weixia Yang; Jiadong Hu; Xin Chen

doi:10.1016/j.bmcl.2025.130318

Histone deacetylase 6 inhibitors in Alzheimer's disease therapy: structure design and challenges

Bioorg Med Chem Lett. 2025 Jun 26:130318. doi: 10.1016/j.bmcl.2025.130318. Online ahead of print.

Authors

Baiyun Dang¹, Hou Chen², Shiru Liu¹, Haijuan Liu¹, Zhiwen Kang¹, Zhen Yang³, Weixia Yang⁴, Jiadong Hu⁵, Xin Chen⁶

Affiliations

¹ Shaanxi Key Labotory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, PR China.
² College of Bioengineering, Yangling Vocational & Technical College, Yangling, Shannxi 712100, PR China.
³ School of Medicinal and Chemical Engineering, Yangling Vocational & Technical College, Yangling, Shannxi 712100, PR China.
⁴ Shaanxi Key Labotory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, PR China. Electronic address: snywx@nwsuaf.edu.cn.
⁵ School of Medicinal and Chemical Engineering, Yangling Vocational & Technical College, Yangling, Shannxi 712100, PR China. Electronic address: hujiadong@aliyun.com.
⁶ Shaanxi Key Labotory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, PR China. Electronic address: chenxin1888@nwsuaf.edu.cn.

PMID: 40581302
DOI: 10.1016/j.bmcl.2025.130318

Abstract

Recently, histone deacetylases 6 (HDAC6) has been extensively studied for involvement in pathogenesis of central nervous system (CNS) diseases, especially for Alzheimer's disease (AD). A lot of literatures have disclosed that HDAC6 inhibitors (HDAC6is) are effective and promising in AD treatment. Though many HDAC6is were reported, only a handful of them displayed appropriate in vivo activities in models of neurological diseases. BBB permeability and off-target toxicity are the major obstacle and challenge for the development of available HDAC6is. In this review, we summarized recent brain-permeable HDAC6is from drug design perspective, and discussed the challenges and structural modification attempts in developing HDAC6is with better blood-brain barrier (BBB) permeability.

Keywords: AD; HDAC6; Permeability; Selectivity; Structure design.

Publication types

Review