Mertansine

Mertansine, also called DM1 (and in some of its forms emtansine), is a thiol-containing maytansinoid that for therapeutic purposes is attached to a monoclonal antibody through reaction of the thiol group with a linker structure to create an antibody-drug conjugate (ADC).

Mertansine
Names
Other names
Maytansinoid DM1
N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine
Identifiers
CAS Number
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard 100.168.831
PubChem CID
UNII
InChI
  • InChI=1S/C35H48ClN3O10S/c1-19-10-9-11-26(46-8)35(44)18-25(47-33(43)37-35)20(2)31-34(4,49-31)27(48-32(42)21(3)38(5)28(40)12-13-50)17-29(41)39(6)23-15-22(14-19)16-24(45-7)30(23)36/h9-11,15-16,20-21,25-27,31,44,50H,12-14,17-18H2,1-8H3,(H,37,43)/b11-9+,19-10+/t20-,21+,25+,26-,27+,31+,34+,35+/m1/s1 N
    Key: ANZJBCHSOXCCRQ-FKUXLPTCSA-N N
SMILES
  • C[C@@H]1[C@@H]2C[C@]([C@@H](/C=C/C=C(/Cc3cc(c(c(c3)OC)Cl)N(C(=O)C[C@@H]([C@]4([C@H]1O4)C)OC(=O)[C@H](C)N(C)C(=O)CCS)C)\C)OC)(NC(=O)O2)O
Properties
Chemical formula
 C35H48ClN3O10S
Molar mass 738.29 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

ADCs with this design include trastuzumab emtansine, lorvotuzumab mertansine, and cantuzumab mertansine. Some are still experimental; others are in regular clinical use.

Mechanism of action

Mertansine is a tubulin inhibitor, meaning that it inhibits the assembly of microtubules by binding to tubulin (at the rhizoxin binding site).[1]

The monoclonal antibody binds specifically to a structure (usually a protein) occurring in a tumour, thus directing mertansine into this tumour. This concept is called targeted therapy.

Uses and chemistry

The following (experimental) drugs are antibody-drug conjugates (ADC) combining monoclonal antibodies with mertansine as the cytotoxic component. Mertansine is linked via 4-mercaptovaleric acid.[2]

ADCs include:

Mertansine linked to a monoclonal antibody (mab). The part where mertansine differs from its parent compound maytansine is shown red. The linker 4-mercaptovaleric acid is shown blue.

Emtansine

DM1 can also be linked via a more complicated structure – 4-(3-mercapto-2,5-dioxo-1-pyrrolidinylmethyl)-cylohexanecarboxylic acid or SMCC –, in which case the International Nonproprietary Name of the conjugate formed contains the word emtansine. The abbreviation comes from the chemical designation "succinimidyl-trans-4-(maleimidylmethyl) cyclohexane-1-carboxylate" which is used in the primary literature[5] as well as by the World Health Organization (WHO)[6] despite the fact that the linker contains only one imide group according to the WHO.[2]

DM1 and its attachment via these linkers result from ImmunoGen Inc research.

An example is:

References
  1. National Cancer Institute: Definition of Maytansine
  2. "International Nonproprietary Names (INN) for pharmaceutical substances: Names for radicals, groups & others" (PDF). WHO. 2012: 66f. {{cite journal}}: Cite journal requires |journal= (help)
  3. "International Nonproprietary Names for Pharmaceutical Substances (INN): List 89" (PDF). WHO. 2003: 188. {{cite journal}}: Cite journal requires |journal= (help)
  4. "ImmunoGen reports encouraging clinical data of IMGN901". The Medical News. 6 December 2009.
  5. Girish, Sandhya; Gupta, Manish; Wang, Bei; Lu, Dan; Krop, Ian E.; Vogel, Charles L.; Burris Iii, Howard A.; Lorusso, Patricia M.; Yi, Joo-Hee; Saad, Ola; Tong, Barbara; Chu, Yu-Waye; Holden, Scott; Joshi, Amita (May 2012). "Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody–drug conjugate in development for the treatment of HER2-positive cancer". Cancer Chemother Pharmacol. 69 (5): 1229–1240. doi:10.1007/s00280-011-1817-3. PMC 3337408. PMID 22271209.
  6. "International Nonproprietary Names for Pharmaceutical Substances (INN): List 103" (PDF). WHO. 2010: 172. {{cite journal}}: Cite journal requires |journal= (help)
  7. National Cancer Institute: trastuzumab-MCC-DM1 antibody-drug conjugate
  8. ImmunoGen: Trastuzumab-DM1 Archived 2010-10-20 at the Wayback Machine
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