2. Academic Validation
  3. Structural Optimization of 1,3-Diaryl-1,2,4-triazole-Capped Histone Deacetylase 6 Inhibitors to Obtain Novel Antiesophageal Cancer Candidates

Structural Optimization of 1,3-Diaryl-1,2,4-triazole-Capped Histone Deacetylase 6 Inhibitors to Obtain Novel Antiesophageal Cancer Candidates

  • J Med Chem. 2025 Jun 12;68(11):10991-11016. doi: 10.1021/acs.jmedchem.4c03231.
Xinhui Zhang 1 2 3,  Huiqin Kang 1,  Bingqian Li 1,  Yuhan Xiong 1,  Shuxian Zheng 1,  Di Zhang 1,  Yuanfan Liu 2,  Shiyu Li 2,  Ying Liu 4,  Hongmin Liu 1,  Ya Gao 1,  Liying Ma 1 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; Key Laboratory of Henan Province for Drug Quality and Evaluation, Henan Province; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
  • 2 School of Biological Engineering, Henan University of Technology, Zhengzhou, Henan 450001, China.
  • 3 Newland Pharmaceutical Co., Ltd., Xuchang, Henan 461500, China.
  • 4 The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, Henan 450001, China.
  • 5 Key Laboratory of Cardio-cerebrovascular Drug, China Meheco Topfond Pharmaceutical Co., Zhumadian 463000, China.
PMID: 40382720 DOI: 10.1021/acs.jmedchem.4c03231
Abstract

Esophageal Cancer, a leading global Cancer, lacks effective therapies. Inhibition of histone deacetylase 6 (HDAC6) is a promising antitumor strategy, yet its role in esophageal Cancer remains underexplored. Through structural optimization of our previously developed 1,3-diaryl-1,2,4-triazole-capped HDAC6 inhibitors, we identified compound 38k, exhibiting remarkably enhanced HDAC6 inhibition (IC50 = 3.12 nM) and 352-fold selectivity over HDAC1. Molecular docking analysis, CETSA, and BLI confirmed its strong HDAC6 binding. Moreover, 38k displayed robust in vitro and in vivo antiesophageal Cancer efficacy, along with an advantageous pharmacokinetic and safety profile. Notably, combining 38k with a PI3K Inhibitor synergistically enhanced the efficacy (75.02% tumor growth inhibition vs 50.94% monotherapy), likely by counteracting HDAC6 inhibition-induced PI3K/Akt activation. These findings validate HDAC6 as a therapeutic target and highlight 38k as a promising candidate for esophageal Cancer treatment, particularly in combination regimens.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-174149
    HDAC6/HDAC1 Inhibitor