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
  • 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: [email protected].
  • 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: [email protected].
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.