Discovery of Novel N-(Anthracen-9-ylmethyl) Benzamide Derivatives as ZNF207 Inhibitors Promising in Treating Glioma

  • J Med Chem. 2024 Feb 20. doi: 10.1021/acs.jmedchem.3c02241.
Menghan Zhang  1 ,  Yushi Ding  2 ,  Mengkang Gao  3 ,  Xiaolin Lu  4 ,  Jun Tan  4 ,  Fei Yu  1 ,  Congying Gu  4 ,  Lujun Gu  1 ,  Xiameng Ren  1 ,  Chenyan Hao  4 ,  Liqin Ming  4 ,  Kang Xu  4 ,  Wenhao Mao  1 ,  Yuqing Jin  1 ,  Min Zhang  2 ,  Linjun You  2  5 ,  Zhanbo Wang  2  5 ,  Yuanyuan Sun  6 ,  Jingwei Jiang  6 ,  Yong Yang  1  7  8 ,  Dayong Zhang  4 ,  Xinying Tang  1
Affiliations
  • 1. School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China 211112.
  • 2. Institute of Pharmaceutical Sciences, China Pharmaceutical University, Nanjing, China 211112.
  • 3. School of Pharmacy, China Pharmaceutical University, Nanjing, China 211112.
  • 4. School of Science, China Pharmaceutical University, Nanjing, China 211112.
  • 5. Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, China 211112.
  • 6. Shuangyun BioMed Sci & Tech (Suzhou) Co., Ltd, Suzhou, China 215000.
  • 7. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China 211112.
  • 8. School of Pharmacy, Xuzhou Medical University, Xuzhou, China 221004.
PMID: 38377560 DOI: 10.1021/acs.jmedchem.3c02241
Abstract

Targeting tumor stemness is an innovative approach to Cancer treatment. Zinc Finger Protein 207 (ZNF207) is a promising target for weakening the stemness of glioma cells. Here, a series of novel N-(anthracen-9-ylmethyl) benzamide derivatives against ZNF207 were rationally designed and synthesized. The inhibitory activity was evaluated, and their structure-activity relationships were summarized. Among them, C16 exhibited the most potent inhibitory activity, as evidenced by its IC50 values ranging from 0.5-2.5 μM for inhibiting sphere formation and 0.5-15 μM for cytotoxicity. Furthermore, we found that C16 could hinder tumorigenesis and migration and promote Apoptosis in vitro. These effects were attributed to the downregulation of stem-related genes. The in vivo evaluation demonstrated that C16 exhibited efficient permeability across the blood-brain barrier and potent efficacy in both subcutaneous and orthotopic glioma tumor models. Hence, C16 may serve as a potential lead compound targeting ZNF207 and has promising therapeutic potential for glioma.

Products