Article ｜ 01 Dec 2023

WIKIMOLE — Mertansine

By TargetMol

MRTX1133

DM1（Mertansine）, T1992, is a derivative of the natural alkaloid Maytansine. Maytansine is found in the genus Maytenus of the Celastraceae family and related plants, and it exhibits a potent ability to inhibit the proliferation of tumor cells. However, Maytansine is highly active and toxic, easily causing severe side effects. Therefore, medicinal chemists have modified Maytansine to obtain a series of derivatives. Among them, the most widely used are Mertansine DM1 and Mertansine DM4 (Ravtansine).

 

 

 

 

Mechanism of Action

DM1 disrupts microtubules in rapidly dividing cancer cells, thereby interfering with chromosome segregation during mitosis. This interruption halts the cell cycle at the M phase, leading to apoptosis in cancer cells and exerting an anti-tumor effect.

 

 

 

Application

DM1 is primarily used as the cytotoxic component in Antibody-Drug Conjugates (ADCs). ADCs generally consist of three parts: a monoclonal antibody drug targeting specific antigens, a cytotoxic drug and a linker connecting the antibody and the cytotoxic agents ("Payload"). The antibody locates tumor cells, and the linker allows the antibody to carry the cytotoxic agents into the tumor cells. The toxic small molecule typically disrupts DNA, microtubule proteins, etc., thereby preventing tumor cell division and killing the cells. DM1 is precisely such a toxic small molecule.

 

 

 

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Reference

[1] Yu-Qing Wang, Meng-Ying Ji, Chang Wang,Endoplasmic reticulum-targeted glutathione and pH dual responsive vitamin lipid nanovesicles for tocopheryl DM1 delivery and cancer therapy,International Journal of Pharmaceutics,Volume 582,2020,119331,ISSN 0378-5173.

[2] Huang CT, Guo X, Ba?inka C, et al. Development of 5D3-DM1: A Novel Anti-Prostate-Specific Membrane Antigen Antibody-Drug Conjugate for PSMA-Positive Prostate Cancer Therapy. Mol Pharm. 2020;17(9):3392-3402. doi:10.1021/acs.molpharmaceut.0c00457

[3] Ran W, Liu X, Chang L, et al. Self-assembling mertansine prodrug improves tolerability and efficacy of chemotherapy against metastatic triple-negative breast cancer. J Control Release. 2020;318:234-245. doi:10.1016/j.jconrel.2019.12.027

[4] Liliana Ascione, Edoardo Crimini, Dario Trapani, Antonio Marra, Carmen Criscitiello, Giuseppe Curigliano, Predicting Response to Antibody Drug Conjugates: A Focus on Antigens’ Targetability, The Oncologist, Volume 28, Issue 11, November 2023, Pages 944–960, https://doi.org/10.1093/oncolo/oyad246