2. Academic Validation
  3. Polymorphs, co-crystal structure and pharmacodynamics study of MBRI-001, a deuterium-substituted plinabulin derivative as a tubulin polymerization inhibitor

Polymorphs, co-crystal structure and pharmacodynamics study of MBRI-001, a deuterium-substituted plinabulin derivative as a tubulin polymerization inhibitor

  • Bioorg Med Chem. 2019 May 1;27(9):1836-1844. doi: 10.1016/j.bmc.2019.03.035.
Mingxu Ma 1,  Zhongpeng Ding 1,  Shixiao Wang 2,  Lingling Ma 3,  Yuxi Wang 4,  Lili Zhong 1,  Zhongping Li 4,  Jinliang Yang 5,  Wenbao Li 6
Affiliations

Affiliations

  • 1 School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
  • 2 Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China.
  • 3 Precision Medicine Research Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 4 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy and Cancer, Chengdu 610041, China.
  • 5 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy and Cancer, Chengdu 610041, China. Electronic address: jlyang01@163.com.
  • 6 School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; Innovation Center for Marine Drug Screening and Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266071, China; Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China. Electronic address: wbli92128@ouc.edu.cn.
PMID: 30910474 DOI: 10.1016/j.bmc.2019.03.035
Abstract

MBRI-001, a deuterium-substituted plinabulin derivative, has been reported to have better pharmacokinetic and similar antitumor effects in comparison with plinabulin. In this approach, we further carried out its polymorphs, co-crystal structure of MBRI-001-tubulin and tubulin inhibition study. Among the different polymorphs, Form F (MBRI-001/H2O) was prepared and evaluated, which had better physical stability and suitable process for scale-up production. Co-crystal structure of MBRI-001-tubulin (PDB:5XI5) was prepared and analyzed. The result of tubulin polymerization assay demonstrated that MBRI-001 could inhibit tubulin polymerization which was similar as plinabulin. Subsequently, the anti-proliferative activities of plinabulin and MBRI-001 were evaluated against two different human lung Cancer cell lines. In vivo study, MBRI-001 revealed similar antitumor inhibition in comparison with plinabulin in A549 xenograft tumor model. Therefore, we suggested that MBRI-001 could be developed as a promising anti-cancer agent in near future.

Keywords

Anti-cancer agent; Co-crystal structure; MBRI-001; Polymorphs; Tubulin inhibition.

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