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Mertansine

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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 Edit this at Wikidata
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/s1Key: ANZJBCHSOXCCRQ-FKUXLPTCSA-N
SMILES
  • C12C((/C=C/C=C(/Cc3cc(c(c(c3)OC)Cl)N(C(=O)C(4(1O4)C)OC(=O)(C)N(C)C(=O)CCS)C)\C)OC)(NC(=O)O2)O
Properties
Chemical formula C35H48ClN3O10S
Molar mass 738.29 g·mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C , 100 kPa). ☒N verify (what is  ?) Infobox references
Chemical compound

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).

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).

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.

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 as well as by the World Health Organization (WHO) despite the fact that the linker contains only one imide group according to the WHO.

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

An example is:

References

  1. Zámečník, Josef; et al. (kolektiv autorů) (2019). "18 – Prediktivní patologie". Patologie [Patology] (in Czech). Vol. 1. Praha: PRAGER PUBLISHING. p. 276. ISBN 978-80-270-6457-1.
  2. National Cancer Institute: Definition of Maytansine
  3. ^ "International Nonproprietary Names (INN) for pharmaceutical substances: Names for radicals, groups & others" (PDF). WHO. 2012: 66f. {{cite journal}}: Cite journal requires |journal= (help)
  4. "International Nonproprietary Names for Pharmaceutical Substances (INN): List 89" (PDF). WHO. 2003: 188. {{cite journal}}: Cite journal requires |journal= (help)
  5. "ImmunoGen reports encouraging clinical data of IMGN901". The Medical News. 6 December 2009.
  6. 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.
  7. "International Nonproprietary Names for Pharmaceutical Substances (INN): List 103" (PDF). WHO. 2010: 172. {{cite journal}}: Cite journal requires |journal= (help)
  8. National Cancer Institute: trastuzumab-MCC-DM1 antibody-drug conjugate
  9. ImmunoGen: Trastuzumab-DM1 Archived 2010-10-20 at the Wayback Machine
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