Polymorphs, co-crystal structure and pharmacodynamics study of MBRI-001, a deuterium-substituted plinabulin derivative as a tubulin polymerization inhibitor.
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.
['Ma|Mingxu|M|', 'Ding|Zhongpeng|Z|', 'Wang|Shixiao|S|', 'Ma|Lingling|L|', 'Wang|Yuxi|Y|', 'Zhong|Lili|L|', 'Li|Zhongping|Z|', 'Yang|Jinliang|J|', 'Li|Wenbao|W|']
D000818:Animals D001665:Binding Sites D045744:Cell Line, Tumor D002470:Cell Survival D018360:Crystallography, X-Ray D003903:Deuterium D054659:Diketopiperazines D006801:Humans D051379:Mice D008819:Mice, Nude D008968:Molecular Conformation D056004:Molecular Dynamics Simulation D009369:Neoplasms D017434:Protein Structure, Tertiary D014404:Tubulin D050257:Tubulin Modulators
Polymorphs Co-crystal structure MBRI-001 Tubulin inhibition Anti-cancer agent