2. Academic Validation
  3. Identification of selenium-containing benzamides as potent microtubule-targeting antitumor agents

Identification of selenium-containing benzamides as potent microtubule-targeting antitumor agents

  • Bioorg Chem. 2025 Mar 10:159:108355. doi: 10.1016/j.bioorg.2025.108355.
Bin Jiang 1,  Yijia Zheng 2,  Tiezheng Xue 1,  Jizhou Wu 2,  Huijuan Song 2,  Sheng Zhou 3,  Yujing Li 2,  Jiaqi Gong 2,  Meng Wei 2,  Xiaorui Ji 2,  Meijiao Wei 2,  Lujun Wang 4,  Jianhua Gong 2,  Mingliang Liu 2,  Apeng Wang 2,  Kai Zhang 5,  Kai Lv 6,  Yanbo Zheng 7
Affiliations

Affiliations

  • 1 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Department of Pharmaceutical Chemistry, School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China.
  • 2 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 3 Department of Pharmaceutical Chemistry, School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China.
  • 4 Department of Pharmacy, Medical Supplies Center of PLA General Hospital, China.
  • 5 Department of Pharmaceutical Chemistry, School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China. Electronic address: 18100956@hebmu.edu.cn.
  • 6 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: lvkai@imb.pumc.edu.cn.
  • 7 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: zhengyb@imb.pumc.edu.cn.
PMID: 40090150 DOI: 10.1016/j.bioorg.2025.108355
Abstract

IMB5046, a microtubule inhibitor discovered by our team, served as the lead compound for designing a series of selenium-containing benzoates and benzamides. Among these, compound 2g emerged as a lead candidate, demonstrating potent antiproliferative activity. Mechanistic studies revealed that 2g bound to the colchicine site of tubulin, caused G2/M cell cycle arrest, and generated ROS. Notably, 2g exhibited exceptional efficacy in P-gp overexpressing MCF7/ADR and KBV200 cell lines, with drug-resistance indices (DRI) of 0.83 and 0.58, respectively, significantly outperforming colchicine (DRIs: 25.4 and 8.03) and paclitaxel (DRIs: 41.0 and 4.96). In an MCF-7 xenograft model, 2g (25 mg/kg, IP) achieved a tumor growth inhibition rate of 57.2 %, surpassing IMB5046 (47.6 %). To enhance solubility and pharmacokinetics, prodrug 2g-P was developed, showing 69 % bioavailability but reduced in vivo efficacy. Further investigation is warranted to elucidate the factors underlying the discrepancy, such as the efficiency of prodrug-to-drug conversion and intracellular accumulation of active 2g. In summary, our study not only identified a novel selenium-containing lead compound, but also provided important insights into prodrug design. These findings lay a solid foundation for the development of next-generation microtubule-targeting agents capable of overcoming drug resistance.

Keywords

Colchicine binding site; IMB5046; Microtubule-targeting agents; P-gp overexpressing cells; Prodrug.

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