2. Academic Validation
  3. Benzothiazole derivatives as histone deacetylase inhibitors for the treatment of autosomal dominant polycystic kidney disease

Benzothiazole derivatives as histone deacetylase inhibitors for the treatment of autosomal dominant polycystic kidney disease

  • Eur J Med Chem. 2024 May 5:271:116428. doi: 10.1016/j.ejmech.2024.116428.
Xudong Cao 1,  Zhiyuan Fan 1,  Lingfang Xu 1,  Wenchao Zhao 1,  Haoran Zhang 1,  Yunfang Yang 1,  Ying Ren 1,  Yuxian Xiao 1,  Nan Zhou 1,  Long Yin 1,  Xueyan Zhou 2,  Xu Zhu 3,  Dong Guo 4
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.
  • 2 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China. Electronic address: zxy851107@126.com.
  • 3 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China. Electronic address: xuzhu@xzhmu.edu.cn.
  • 4 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China. Electronic address: guo@xzhmu.edu.cn.
PMID: 38653068 DOI: 10.1016/j.ejmech.2024.116428
Abstract

Recent evidence suggests that histone deacetylases (HDACs) are important regulators of autosomal dominant polycystic kidney disease (ADPKD). In the present study, a series of benzothiazole-bearing compounds were designed and synthesized as potential HDAC inhibitors. Given the multiple participation of HDACs in ADPKD cyst progression, we embarked on a targeted screen using HeLa nuclear extracts to identify potent pan-HDAC inhibitors. Compound 26 emerged as the most efficacious candidate. Subsequent pharmacological characterization showed that compound 26 effectively inhibits several HDACs, notably HDAC1, HDAC2, and HDAC6 (IC50 < 150 nM), displaying a particularly high sensitivity towards HDAC6 (IC50 = 11 nM). The selected compound significantly prevented cyst formation and expansion in an in vitro cyst model and was efficacious in reducing cyst growth in both an embryonic kidney cyst model and an in vivo ADPKD mouse model. Our results provided compelling evidence that compound 26 represents a new HDAC Inhibitor for the treatment of ADPKD.

Keywords

Autosomal dominant polycystic kidney disease; Benzothiazole derivatives; HDAC inhibitors; Histone deacetylases.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-161524
    HDAC6抑制剂
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