11 / 2021-10-08 11:20:43

Progress of CMBT-001, a deuterium-substituted plinabulin, as a potent drug candidate for CIN and anticancer

CMBT-001; drug candidate; CIN; anticancer; co-crystal complexes

       Plinabulin is developed from marine natural “phenylahistin”. Currently, the combination of plinabulin and G-CSF for prevention of CIN has been filed NDA in China and USA, and the combination of plinabulin and docetaxel for treatment of NSCLC has been reported and completed Phase III clinical trial. CMBT-001 (named as MBRI-001 previous) is a deuterium-substituted plinabulin derivative, which has better PK profile than plinabulin in vivo. The total synthesis yield of CMBT-001 at kilogram of production was 11% in eight linear steps. Its Crystal Form E (composed of CMBT-001 and H₂O) was the most stable at different temperature and humidity. The anti-proliferative activities of CMBT-001 were observed at low nanomolar level against a variety of cancer cell lines. Immunofluorescence and cell cycle assays demonstrated that CMBT-001 could inhibit the formation of microtubules and induce G2/M arrest through the down-regulation of cyclin B1 (CCNB1). The co-crystal complex of CMBT-001-tubulin (PDB:5XI5) was prepared and analyzed to explore the interaction mechanism of CMBT-001 and tubulin. In vivo studies, CMBT-001 has shown a significant efficiency without apparent toxicity by intravenous injection (alone or combination administration) in different mice models for the treatment of lung cancer, liver cancer and other cancers. More significantly, the combination treatment of CMBT-001 with gefitinib or sorafenib exhibited a higher antitumor effect in comparison with the monotherapy of CMBT-001 in vivo. PK studies indicated that its pharmacokinetic properties were improved in vivo with longer t_1/2, and double AUC compared with plinabulin. CMBT-001 could be distributed rapidly and widely in various tissues, of which the concentration in lung was remarkably higher than other tissues in rat body. The excretion study indicated that most of CMBT-001 might be decomposed and excreted as metabolites. Toxicity test showed that the maximum tolerated dose (MTD) of CMBT-001 is 15 mg/kg or 6 mg/kg in mice or rats, respectively. In general, we believe CMBT-001 could be developed as a promising anticancer and CIN agent in near future.