Maytansine And Its Analogues

Maytansine is benzoansamacrolide originally isolated from the shrub Maytenus ovatus. It is a highly effective microtubule-targeting compound and is being widely studied as a cytotoxic component of antibody-drug conjugates.

Biological activity

Similar to vinca alkaloids, maytansine binds tubulin at the vinblastine binding site, thereby depolymerizing tubulin and inducing mitotic arrest. Microtubules are dynamic cytoskeletal polymers that can switch randomly between growing and shortening states, which is called "dynamic instability". They have precise segregation of chromosomes in cell division, transportation of cellular cargo, and positioning and intracellular organelles. The inhibition of microtubule function leads to cell cycle arrest and cell death. Drugs targeting microtubules include vinca alkaloids, taxanes, and epothilones, which can inhibit the dynamic instability of microtubules, induce mitotic arrest, inhibit cell proliferation, and induce apoptosis.

Maytansine can effectively resist Lewis lung cancer and B16 murine melanoma solid tumors in vivo and has anti-leukemia activity against P388 murine lymphocytic leukemia. Screening of 60 human cancer cell types by the National Cancer Institute confirmed the anti-proliferative activity of maytansine on microtubule targeting. Although maytansine inhibits the assembly of microtubules and kills cancer cells, its clinical use is affected by severe side effects and poor efficacy. When evaluated as a single agent, maytansine failed to show any significant response in patients with different types of cancer.

Figure 1: structure of Maytansine, DM1 and DM4 (Manu Lopus, 2010).

Maytansine analogues

The anticancer properties of maytansinoids are attributed to their ability to disrupt microtubule function. The maytansine-like emtansine (DM1), for example, binds to the ends of microtubules and inhibits their dynamic instability.

Ravtansine (DM4) is a maytansinoid, which is a chemical derivative of maytansine, which has been studied as a cytotoxic payload for various antibody-drug conjugates (ADC).

Other maytansinoids include

• Ansamitocin
• Mertansine/emtansine (DM1)
• Ravtansine/soravtansine (DM4)

ADCs drugs with Maytansine and its analogues

The first and only ADC based on maytansinoid, trastuzumab emtansine (Kadcyla) was approved for HER2-positive metastatic breast cancer in 2013.

References

1. Kumar, A., White, J., James Christie, R., Dimasi, N., & Gao, C. Antibody-Drug Conjugates. Platform Technologies in Drug Discovery and Validation. 2017; 50:441-480.
2. 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):2689-2699.
3. Victor S. Goldmacher, Charlene A. Audette, Yinghua Guan, et al. High-Affinity Accumulation of a Maytansinoid in Cells via Weak Tubulin Interaction. PLoS One. 2015; 10(2):e0117523.
4. Victor S. Goldmacher, Thomas Chittenden, Ravi V. J. Chari, Yelena V. Kovtun, John M. Lambert. Chapter Twenty-Three - Antibody–Drug Conjugates for Targeted Cancer Therapy. Annual Reports in Medicinal Chemistry. 2012; 47:349-366.
5. Manu Lopus. Antibody-DM1 Conjugates as Cancer Therapeutics. Cancer Lett. 2011 Aug 28; 307(2):113-118.

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Maytansine And Its Analogues

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