生物活性

• 描述Tubulin normally undergoes a cycle of detyrosination/tyrosination on the carboxy terminus of its alpha-subunit and this results in subpopulations of tyrosinated tubulin and detyrosinated tubulin^[1]. Maytansinoid DM4 is a thiol-containing maytansine derivative with highly potent cytotoxicity. Maytansinoid DM4 is a tubulin inhibitor, inhibits the assembly of microtubules by binding to tubulin, with a linker structure can create an antibody-drug conjugate (ADC). Maytansine is a natural benzoansamacrolide product isolated from the bark of the African shrub Maytenus ovatus. Maytansine binds to the same site on tubulin as the vinca alkaloids, with similar in vitro inhibition constants, but is a more-potent cytotoxin^[2]. Maytansinoid DM1 and DM4 inactivated CYP3A from human liver microsomes with K(i)/k(inact) values of 4. 8 ± 0. 9 μM/0. 035 ± 0. 002 min(-1) and 3. 3 ± 0. 2 μM/0. 114 ± 0. 002 min(-1), respectively. DM1 and DM4 inactivated recombinant CYP3A4 with K(i)/k(inact) values of 3. 4 ± 1. 0 μM/0. 058 ± 0. 005 min(-1) and 1. 4 ± 0. 3 μM/0. 117 ± 0. 006 min(-1), respectively^[3]. Although S-methyl-DM1 and S-methyl-DM4 inhibited polymerization more weakly than maytansine, at 100 nmol/L they suppressed dynamic instability more strongly than maytansine (by 84% and 73%, respectively, compared with 45% for maytansine). Both maytansine and S-methyl-DM1 bound to tubulin with similar K(D) values (0. 86 ± 0. 2 and 0. 93 ± 0. 2 μmol/L, respectively)^[4].
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01638936	Multiple Myeloma	Phase 1 Phase 2	Active, not recruiting	November 2018	United States, California ... more >> City of Hope Duarte, California, United States, 91010 USC Norris Comprehensive Cancer Center Los Angeles, California, United States, 90033 United States, Florida Mayo Clinic Jacksonville, Florida, United States, 32224 Memorial Healthcare System Pembroke Pines, Florida, United States, 33028 United States, Georgia Emory University Winship Cancer Institute Atlanta, Georgia, United States, 30322 United States, Illinois The University of Chicago Chicago, Illinois, United States, 60637 United States, Massachusetts Dana-Farber Cancer Institute Boston, Massachusetts, United States, 02115 United States, New Jersey Hackensack University Medical Center Hackensack, New Jersey, United States, 07601 United States, New York Mount Sinai Medical Center New York, New York, United States, 10029 United States, Texas University of Texas Health Science Center San Antonio, Texas, United States, 78229 Collapse <<
  NCT03324113	Neoplasm Malignant	Phase 1	Active, not recruiting	January 2019	Japan ... more >> Investigational Site Number 3920003 Kashiwa-Shi, Japan Investigational Site Number 3920002 Nagoya-Shi, Japan Investigational Site Number 3920001 Sunto-Gun, Japan Collapse <<
  NCT00721669	Solid Tumor	Phase 1	Completed	-	United States, Florida ... more >> Florida Cancer Specialists Fort Myers, Florida, United States, 33905 United States, Oklahoma University of Oklahoma Oklahoma City, Oklahoma, United States, 73104 United States, Tennessee Sarah Cannon Research Institute Nashville, Tennessee, United States Collapse <<

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• 参考文献

• [1] L Lafanechère, D Job. The third tubulin pool. Neurochem Res. 2000 Jan;25(1):11-8.

  [2] Beck A, et al. Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov. 2017 May;16(5):315-337.

  [3] John A Davis 1, Dan A Rock, et al. In vitro characterization of the drug-drug interaction potential of catabolites of antibody-maytansinoid conjugates. Drug Metab Dispos. 2012 Oct;40(10):1927-34.

  [4] Manu Lopus, Emin Oroudjev,et al. Maytansine and cellular metabolites of antibody-maytansinoid conjugates strongly suppress microtubule dynamics by binding to microtubules. Mol Cancer Ther. 2010 Oct;9(10):2689-99.