Monomethyl Auristatin F

Chemical Name: (S)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)butanamido)butanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoic acid

Molecular Weight: 731.96
Formula: C39H65N5O8
CAS#: 141205-32-5
Solubility: DMSO up to 20 mM

Biological Activity
Monomethyl auristatin F (MMAF) or desmethyl-auristatin F is an anti-tubulin agent that inhibits cell division by blocking the polymerization of tubulin. It is a new auristatin derivative with a charged C-terminal phenylalanine that attenuates its cytotoxic activity compared to its uncharged counterpart, monomethyl auristatin E (MMAE). In addition, the N-terminal amino group has only one methyl substituent instead of two as in auristatin F itself.[1][2][3][4]

Structure of conjugate of MMAF with a monoclonal antibody (mAb). The attachment group consists of maleimide and caproic acid. About eight such structures are bound to a single antibody molecule.[6]
Because of MMAF is highly toxic, it cannot be used as a drug itself.  However, MMAF induces potent antitumor effects when conjugated via protease cleavable linkers to a monoclonal antibody targeting internalizing, tumor-specific cell surface antigens.

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The linker to the monoclonal antibody is stable in extracellular fluid but is cleaved by cathepsin once the conjugate has entered a tumor cell, thus activating the anti-mitotic mechanism. [4][5]

[1] Smith LM, Nesterova A, Alley SC, Torgov MY, Carter PY. Potent cytotoxicity of an auristatin-containing antibody-drug conjugate targeting melanoma cells expressing melanotransferrin/p97. Mol Cancer Ther June 2006 5; 1474-82.doi: 10.1158/1535-7163.MCT-06-0026
[2] Doronina SO, Mendelsohn BA, Bovee TD, Cerveny CG, Alley SC, Meyer DL, Oflazoglu E, et al. Enhanced activity of monomethyl auristatin F through monoclonal antibody delivery: effects of linker technology on efficacy and toxicity. Bioconjug Chem. 2006 Jan-Feb;17(1):114-24.
[3] Oflazoglu E, Stone IJ, Gordon K, Wood CG, Repasky EA, Grewal IS, Law CL, Gerber HP. Potent anticarcinoma activity of the humanized anti-CD70 antibody h1F6 conjugated to the tubulin inhibitor auristatin via an uncleavable linker. Clin Cancer Res. 2008 Oct 1;14(19):6171-80. doi: 10.1158/1078-0432.CCR-08-0916. Epub 2008 Sep 22.
[4] Nilsson R, Mårtensson L, Eriksson SE, Sjögren HO, Tennvall J. Toxicity-reducing potential of extracorporeal affinity adsorption treatment in combination with the auristatin-conjugated monoclonal antibody BR96 in a syngeneic rat tumor model. Cancer. 2010 Feb 15;116(4 Suppl):1033-42. doi: 10.1002/cncr.24790.
[5] Monomethyl auristatin E (Wikipedia)
[6] Dosio F, Brusa P, Cattel L. Immunotoxins and anticancer drug conjugate assemblies: the role of the linkage between components. Toxins (Basel). 2011;3(7):848-883. doi:10.3390/toxins3070848

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