Monomethyl auristatin E

Monomethyl auristatin E
IUPAC name (S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)-N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)butanamido)butanamide
Other names Monomethylauristatin E; Vedotin
Identifiers
Abbreviations	MMAE
CAS number	474645-27-7 N
PubChem	53297465
Jmol-3D images	Image 1
SMILES CO[C@H]([C@H](C(N[C@@H]([C@H](C1=CC=CC=C1)O)C)=O)C)[C@@]2([H])N(C(C[C@H]([C@H]([C@H](CC)C)N(C)C([C@H](C(C)C)NC([C@@H](NC)C(C)C)=O)=O)OC)=O)CCC2
Properties
Molecular formula	C39H67N5O7
Molar mass	717.98 g mol−1
N auristatin E (verify) (what is: Y/N?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Monomethyl auristatin E (MMAE) is a synthetic antineoplastic agent. Because of its toxicity, it cannot be used as a drug itself; instead, it is linked to a monoclonal antibody (MAB) which directs it to the cancer cells. In International Nonproprietary Names for MMAE-MAB-conjugates, MMAE is referred to as vedotin.

Mechanism of action

Monomethyl auristatin E is an antimitotic agent which inhibits cell division by blocking the polymerisation of tubulin. The linker to the monoclonal antibody is stable in extracellular fluid, but is cleaved by cathepsin once the conjugate has entered a tumour cell, thus activating the antimitotic mechanism.^[1][2]

General structure of a MMAE-MAB-conjugate. The linker, consisting of the amino acids valine (Val) and citrulline (Cit), is cleaved by cathepsin inside tumour cells.

Monoclonal antibodies

MMAE has been tested with various monoclonal antibodies.

• targeting the protein CD30 which is found on malignant cells in anaplastic large cell lymphoma and Hodgkin's lymphoma:
  • Brentuximab (cAC10): 3–5 units of MMAE per molecule^[1][2]
• targeting the glycoprotein GPNMB which is found in aggressive melanoma, glioma, breast cancer and other tumours:
  • Glembatumumab (CR011, CDX-011): investigated for the treatment of breast cancer and melanoma^[3][4]

References

1. ^ ^{a b} Seattle Genetics: Brentuximab vedotin (SGN-35)
2. ^ ^{a b} Francisco, Joseph A; et al. (2003). "cAC10-vcMMAE, an anti-CD30–monomethyl auristatin E conjugate with potent and selective antitumor activity". Blood 102 (4): 1458–1465. doi:10.1182/blood-2003-01-0039. PMID 12714494. http://bloodjournal.hematologylibrary.org/cgi/reprint/102/4/1458.pdf. 
3. ^ Medical News Today: CuraGen Announces Expansion Of CR011-vcMMAE Phase II Trial In Advanced Breast Cancer
4. ^ NCI Drug Dictionary: Glembatumumab vedotin