2. Academic Validation
  3. Discovery and evaluation of novel Benzohydroxamic acid-indole derivatives as dual inhibitors of ADAM17 and HDAC2 with antitumor activity

Discovery and evaluation of novel Benzohydroxamic acid-indole derivatives as dual inhibitors of ADAM17 and HDAC2 with antitumor activity

  • Bioorg Chem. 2025 Apr:157:108308. doi: 10.1016/j.bioorg.2025.108308.
Xiaoxuan Song 1,  Xin Tong 2,  Kaisi Yang 2,  Yiming Qi 2,  Wenwu Liu 3,  Yuzhu Sun 4,  Chengkang Wang 2,  Fanghua Xun 2,  Ziyi Wang 2,  Muxuan Jiang 2,  Yingshi Zhang 5,  Tianshu Ren 2,  Di Chen 6,  Shanbo Hou 7,  Aigang Song 7,  Huiyuan Gao 8,  Qingchun Zhao 9
Affiliations

Affiliations

  • 1 Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, PR China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road Shenhe District, Shenyang, Liaoning 110016, PR China.
  • 2 Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, PR China.
  • 3 Department of Pharmacy, Peking University First Hospital, Xishiku Street, Xicheng District, 100034 Beijing, PR China.
  • 4 Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016, China. Shenyang, Liaoning 110016, PR China.
  • 5 Department of Clinical Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenhe District, Shenyang 110016, PR China.
  • 6 Department of Pharmacy, Beijing Hospital; National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences;, Beijing 100730, PR China; General Hospital of Northern Theater Command, China Medical University, PR China.
  • 7 Luoxin Pharmaceuticals Group Stock Co., Ltd., Linyi, PR China.
  • 8 School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road Shenhe District, Shenyang, Liaoning 110016, PR China; Key Laboratory of Pharmacodynamic Substances Research & Translational Medicine of Immune Diseases of Shenyang, Shenyang Pharmaceutical University, Shenyang 110016, PR China; Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: sypugaohy@163.com.
  • 9 Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, PR China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road Shenhe District, Shenyang, Liaoning 110016, PR China; Department of Clinical Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenhe District, Shenyang 110016, PR China.. Electronic address: zhaoqingchun1967@163.com.
PMID: 40049049 DOI: 10.1016/j.bioorg.2025.108308
Abstract

Hepatocellular carcinoma (HCC) has garnered significant attention from researchers due to its high recurrence rate and invasive characteristics. The design of drugs with dual-target combined effects represents a promising strategy in Cancer treatment. Our observations suggest that ADAM17 and HDAC may inhibit the unfavorable prognostic signaling pathway Notch1 in HCC through distinct mechanisms, thereby suppressing tumor cell proliferation and metastasis. Consequently, this study utilized the ADAM17 Inhibitor ZLDI-8 as a lead compound and developed a series of dual ADAM17/HDAC2 inhibitors by integrating strategies such as backbone leaping and pharmacophore fusion. We assessed the anti-hepatocellular carcinoma activity of these compounds, focusing on their anti-proliferative, pro-apoptotic, and anti-metastatic properties. Notably, ZSNI-21 effectively inhibited the proliferation of Bel-7402 cells and demonstrated significant anti-metastatic capabilities against HCC-LM3 cells, with its targeting confirmed. Additionally, its in vivo safety was validated. To date, there have been no reports on dual ADAM17/HDAC2 inhibitors, marking this as a novel endeavor.

Keywords

ADAM17; HCC; HDAC2; Indole derivatives.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-172394
    ADAM17/HDAC2抑制剂
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