Monomethylauristatin E
[CAS# 474645-27-7]

Identification

• Classification: API >> Antineoplastic agents
• Name: Monomethylauristatin E
• Synonyms: N-Methyl-L-valyl-N-[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]amino]-1-methoxy-2-methyl-3-oxopropyl]-1-pyrrolidinyl]-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxobutyl]-N-methyl-L-valinamide
• Protein Sequence: VV
• Molecular Formula: C₃₉H₆₇N₅O₇
• Molecular Weight: 717.98
• CAS Registry Number: 474645-27-7
• EC Number: 811-424-8
• SMILES: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@@H]([C@@H](C)C(=O)N[C@H](C)[C@H](C2=CC=CC=C2)O)OC)OC)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)NC

Properties

• Solubility: Slightly soluble (2 g/L) (25 ºC), Calc.^*
• Density: 1.088±0.06 g/cm³ (20 ºC 760 Torr), Calc.^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software V11.02 (©1994-2013 ACD/Labs)

Safety Data

• Hazard Symbols: GHS06;GHS07;GHS08 Danger
• Hazard Statements: H300-H302-H315-H319-H330-H335-H341-H360-H370-H372
• Precautionary Statements: P203-P260-P261-P264-P264+P265-P270-P271-P280-P284-P301+P316-P301+P317-P302+P352-P304+P340-P305+P351+P338-P308+P316-P316-P318-P319-P320-P321-P330-P332+P317-P337+P317-P362+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	4	H302
Acute toxicity	Acute Tox.	2	H330
Skin irritation	Skin Irrit.	2	H315
Specific target organ toxicity - single exposure	STOT SE	3	H335
Specific target organ toxicity - repeated exposure	STOT RE	1	H372
Reproductive toxicity	Repr.	1B	H360
Germ cell mutagenicity	Muta.	2	H341
Acute toxicity	Acute Tox.	1	H300
Specific target organ toxicity - single exposure	STOT SE	1	H370
Eye irritation	Eye Irrit.	2	H319

Discovory and Applicatios

Monomethylauristatin E (MMAE) was derived from the natural compound dolastatin 10, initially isolated from the marine mollusk Dolabella auricularia. Dolastatin 10 exhibited potent antitumor properties, inspiring researchers to develop synthetic derivatives with improved pharmacological properties. MMAE was one such derivative synthesized by scientists at Seattle Genetics, designed to enhance stability and bioavailability while retaining the potent cytotoxicity of dolastatin 10. Its discovery marked a significant advancement in the field of targeted cancer therapy.

MMAE serves as a cytotoxic payload in antibody-drug conjugates (ADCs), a class of targeted cancer therapies. In ADCs, MMAE is conjugated to monoclonal antibodies specific to tumor antigens. Upon binding to cancer cells, the ADC is internalized, releasing MMAE into the cell where it disrupts microtubule dynamics, leading to cell cycle arrest and apoptosis. This targeted approach minimizes systemic toxicity while maximizing the cytotoxic effects on cancer cells. ADCs containing MMAE, such as brentuximab vedotin, have shown remarkable efficacy in the treatment of lymphomas, including Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Brentuximab vedotin targets CD30-expressing lymphoma cells, delivering MMAE directly to the tumor cells and sparing healthy tissues. Clinical trials have demonstrated significant improvements in progression-free survival and overall survival in patients with relapsed or refractory lymphomas. Research is ongoing to explore the potential of MMAE-based ADCs in the treatment of solid tumors, including breast cancer, lung cancer, and ovarian cancer. Preclinical studies have shown promising results, suggesting that ADCs containing MMAE may offer a targeted approach to treating solid tumors with reduced systemic toxicity compared to traditional chemotherapy.

References

2024. Clinical Pharmacology of the Antibody-Drug Conjugate Enfortumab Vedotin in Advanced Urothelial Carcinoma and Other Malignant Solid Tumors. Clinical Pharmacokinetics, 63.
DOI: 10.1007/s40262-024-01369-0

2024. Monomethyl auristatin E (MMAE), a payload for multiple antibody drug conjugates (ADCs), demonstrates differential red blood cell partitioning across human and animal species. Xenobiotica; the fate of foreign compounds in biological systems, 54.
DOI: 10.1080/00498254.2024.2345849

2004. Efficient Elimination of B-Lineage Lymphomas by Anti-CD20-Auristatin Conjugates. Clinical cancer research : an official journal of the American Association for Cancer Research, 10.
DOI: 10.1158/1078-0432.ccr-04-1028