MMAF Hydrochloride - CAS 1415246-68-2
Catalog number:
B0084-463223
Category:
Inhibitor
Not Intended for Therapeutic Use. For research use only.
Molecular Formula:
C39H66ClN5O8
Molecular Weight:
768.42
COA:
Inquire
Targets:
ADCs Cytotoxin
Description:
MMAF 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). Because of MMAF is highly toxic, it cannot be used as a drug itself. MMAF induces potent antitumor effects when conjugated via protease cleavable linkers to a monoclonal antibody targeting internalizing, tumor-specific cell surface antigens. 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.
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Purity:
>98%
Synonyms:
Monomethylauristatin F Hydrochloride
MSDS:
Inquire
Application:
For research used only
1. Emerging classes of armed antibody therapeutics against cancer
Christian Hess, Dario Venetz, Dario Neri*. Med. Chem. Commun.,2014, 5,408–431
Calicheamicins bind to the DNA minor groove where they induce double-strand breaks leading to chromosomal disruption, ultimately resulting in programmed cell death, while the other two drugs interfere with microtubule restructuring. Auristatins were originally derived from the naturally occurring pentapeptide dolastatin-10. Mono-methyl auristatin E (MMAE) and F (MMAF) are the most prominent dolastatin-10 derivatives, which are implemented in many current clinical-stage ADCs. These fully synthetic analogues differ from natural dolastatin-10 in terms of an N-terminal methyl group, which results in superior proteolytic stability. Additionally, MMAF features a C-terminal charged phenylalanine residue, which attenuates its cytotoxic activity compared to the uncharged MMAE. Maytansinoids such as DM1 and DM4 are derivatives of the natural product maytansine and represent two of the most widely used ADC payloads to date. Upon lysosomal degradation of the antibody, the mechanism of action of these two agents is considered to be identical. However, the linker region of the drug can have a profound impact on ADC performance. It has been reported for disulfide-linked maytansinoids that two additional methyl groups at positions directly adjacent to the disulfide bond (corresponding to DM4) can increase plasma stability of the conjugate.
2. The antibody-drug conjugate: an enabling modality for natural product-based cancer therapeutics
Hans-Peter Gerber, Frank E. Koehnb, Robert T. Abraham*. Nat. Prod. Rep., 2013, 30, 625–639
An additional clinically-relevant auristatin, MMAF, bears a C-terminated phenylalanine residue with a free carboxyl group. MMAF proved effective in preclinical models of Hodgkin's lymphoma and anaplastic large cell lymphoma (ALCL) when conjugated to anti-CD30 antibodies and has now been conjugated to additional antibodies with non-cleavable linkers. Themaleimidocaproyl (MalC) linker is used in SGN-75 of Seattle Genetics to conjugate MMAF to an anti-CD70 antibody. Once in the lysosome, the antibody is degraded to yield the MMAF-caproylmaleido-cysteine adduct as the active cyto-Toxin. Due to its free carboxyl group, MMAF itself has limited cell permeability, and its in vitro potency is roughly 10–200-fold lower than that of the MMAE. However, these shortcomings are effectively overcome by transfer to the ADC format, which effectively delivers the payload intracellularly, leading to a potency increase of 2200-fold as well as reduced toxicity against non-antigen-expressing cells.
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CAS 1415246-68-2 MMAF Hydrochloride

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