2. Academic Validation
  3. Design, synthesis, and antitumor activity study of β-carboline derivatives as selective HDAC1/2 inhibitors

Design, synthesis, and antitumor activity study of β-carboline derivatives as selective HDAC1/2 inhibitors

  • Bioorg Chem. 2025 Aug:163:108763. doi: 10.1016/j.bioorg.2025.108763.
Zhiya Wang 1,  Limeng Wu 2,  Kaisi Yang 2,  Yiming Qi 2,  Zhenshu Li 2,  Wenjie Liu 3,  Xiangbo Xu 2,  Fangyuan Zheng 2,  Wenbo Zeng 2,  Hao Gong 2,  Caizhi Tian 4,  Hefeng Geng 5,  Zihua Xu 2,  Kangyao Zhou 6,  Haihong Tian 7,  Tianshu Ren 8,  Qingchun Zhao 9
Affiliations

Affiliations

  • 1 Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, People's Republic of China; School of Pharmacy, China Medical University, Shenyang 110122, People's Republic of China.
  • 2 Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, People's Republic of China.
  • 3 College of Life and Health Sciences, Northeastern University, Shenyang 110819, People's Republic of China.
  • 4 School of Pharmacy, China Medical University, Shenyang 110122, People's Republic of China.
  • 5 School of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
  • 6 Department of Pharmacy, Peking University First Hospital, Beijing 100034, People's Republic of China.
  • 7 Shenyang Joint Logistic Support Center Medical Device and Pharmaceutical Supervision and Testing Station, Shenyang 110819, People's Republic of China. Electronic address: 2562512767@qq.com.
  • 8 Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, People's Republic of China. Electronic address: sz_pharm@163.com.
  • 9 Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, People's Republic of China. Electronic address: zhaoqingchun1967@163.com.
PMID: 40706541 DOI: 10.1016/j.bioorg.2025.108763
Abstract

As pivotal epigenetic regulators, HDAC inhibitors exert antitumor effects by remodeling chromatin architecture and modulating gene expression profiles. However, current HDAC inhibitors demonstrate limited clinical efficacy in colorectal Cancer due to selectivity with issues and dose-limiting toxicities. Herein, we developed novel β-carboline-based HDAC1/2 dual inhibitors, with particular emphasis on compound ZWZH-21 ，in which the oxygen atom serves as an innovative CU. In vitro antiproliferative assays revealed that ZWZH-21 displayed remarkable growth inhibition against colorectal Cancer cell lines HCT116 and SW480, with IC50 values of 0.524 ± 0.023 μM and 1.063 ± 0.119 μM, respectively. The compound showed potent enzymatic inhibition against HDAC1/2 isoforms (IC50 = 34 nM and 41 nM, respectively) and possessed high selectivity for HDAC1/2 over Other isoform. Western blot analysis demonstrated that ZWZH-21 significantly enhanced acetylation of the biomarker histone H3 and H4 while suppressing HDAC1/2 protein levels. Cellular thermal shift assay (CETSA) confirmed direct target engagement between ZWZH-21 and intracellular HDAC1/2. Furthermore, ZWZH-21 effectively inhibited proliferation and migration in multiple colorectal Cancer cell models, induced Apoptosis, and demonstrated robust antitumor efficacy in xenograft models without observable toxicity. These findings establish ZWZH-21 as a promising lead compound for development as a novel HDAC Inhibitor with potential Anticancer applications.

Keywords

Anticancer; Epigenetic-targeted drugs; HDAC1/2 inhibitors; Β-Carboline derivatives.

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