Monomethylauristatin F
[CAS# 745017-94-1]

Identification

• Classification: API >> Other chemicals
• Name: Monomethylauristatin F
• Synonyms: MMAF
• Molecular Formula: C₃₉H₆₅N₅O₈
• Molecular Weight: 731.96
• CAS Registry Number: 745017-94-1
• 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](CC2=CC=CC=C2)C(=O)O)OC)OC)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)NC

Properties

• Solubility: Slightly soluble (2.8 g/L) (25 °C), Calc.^*, 10 mM (DMSO) (Expl.)
• Density: 1.116±0.06 g/cm³ (20 °C 760 Torr), Calc.^* (Expl.)
• Index of Refraction: 1.522, Calc.^*
• Boiling Point: 896.8±65.0 °C (760 mmHg), Calc.^*
• Flash Point: 496.2±34.3 °C, Calc.^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302-H315-H319-H335
• Safety Statements: P261-P305+P351+P338

Discovery and Applications

Monomethylauristatin F is a synthetic chemical compound that belongs to the class of auristatins, which are known for their potent anticancer properties. It was developed as part of a series of compounds designed for use in antibody-drug conjugates (ADCs), a cutting-edge approach in targeted cancer therapy. Monomethylauristatin F is derived from the natural product auristatin, a potent microtubule inhibitor that disrupts the cell cycle and induces cell death in rapidly proliferating cancer cells.

The discovery of monomethylauristatin F can be traced back to the broader development of auristatin derivatives. These compounds were initially isolated from the marine organism Dolastatins, which are peptides known for their ability to inhibit tubulin polymerization. The modification of auristatin through chemical synthesis led to the development of monomethylauristatin F, which retains its powerful activity against microtubules but with improved pharmacological properties, including better stability and solubility compared to its predecessors.

Monomethylauristatin F is particularly useful in the field of targeted cancer therapy due to its inclusion in ADCs. ADCs are designed by attaching a cytotoxic drug like monomethylauristatin F to a monoclonal antibody that specifically targets cancer cells. This allows for the selective delivery of the drug directly to tumor cells, sparing healthy tissues and reducing side effects compared to traditional chemotherapy. The effectiveness of monomethylauristatin F as an ADC payload has been demonstrated in various preclinical and clinical studies, where it has shown promising results in the treatment of cancers such as breast cancer, lymphoma, and solid tumors.

One of the key features of monomethylauristatin F is its ability to bind to tubulin, a protein that is essential for microtubule formation and function. By disrupting the microtubule network, monomethylauristatin F inhibits cell division, leading to cell cycle arrest and apoptosis (programmed cell death). This mechanism of action is similar to other microtubule-targeting agents, such as paclitaxel, but with a greater potency and more selective activity when delivered directly to cancer cells via an antibody conjugate.

Despite its potential, the use of monomethylauristatin F is not without challenges. Its inclusion in ADCs requires careful optimization of the conjugation process, ensuring that the drug is efficiently delivered to the tumor site without causing excessive toxicity. Moreover, resistance to ADCs can develop over time, leading to the need for combination therapies that target multiple pathways in cancer cells.

In clinical applications, monomethylauristatin F has been evaluated in several ADCs undergoing clinical trials, showing effectiveness in various tumor types. Its ongoing development and testing hold significant promise for improving cancer treatments by providing a more targeted, less toxic alternative to conventional chemotherapy. As research into ADCs and their payloads continues to evolve, compounds like monomethylauristatin F will play an essential role in the future of personalized cancer therapy.

References

2005. Enhanced Activity of Monomethylauristatin F through Monoclonal Antibody Delivery: Effects of Linker Technology on Efficacy and Toxicity. Bioconjugate Chemistry, 17(1).
DOI: 10.1021/bc0502917

2022. Discovery and Development of Dolastatin 10-Derived Antibody Drug Conjugate Anticancer Drugs. Journal of Natural Products, 85(3).
DOI: 10.1021/acs.jnatprod.1c01135

2017. Enzymatic conjugation using branched linkers for constructing homogeneous antibody-drug conjugates with high potency. Organic & Biomolecular Chemistry, 15(26).
DOI: 10.1039/c7ob01027c