An auristatin with anticancer activity
MMAF is a highly potent antimitotic agent [1].
MMAF is an auristatin F (AF) derivative and is used as an antimitotic drug in the form of antibody drug conjugates (ADCs). It is reported that both the N-terminal monomethylvaline and the C-terminal carboxyl group of MMAF can be attached to the linker. Dipeptide linkers used for the attachment of MMAF to mAbs result in conjugates pronounced and potent activities against an array of tumor types. In the in vitro cytotoxicity assays, the ADC generated by attaching MMAF to the 1F6 mAb shows a potent inhibition to the cell viability with IC50 values of 10ng/ml, 8ng/ml, and 123ng/ml in 786-O, Caki-1 and L428 cell lines, respectively. Moreover, it is reported that the dipeptide linker attached to MMAF with C-terminal amino acids could modulate the efficacy, potency, and tolerability. The manipulation of the C-terminal peptide sequence leads to the improved potency, specificity and therapeutic windows of the conjugates [1].
参考文献:
[1] Doronina SO, Bovee TD, Meyer DW, Miyamoto JB, Anderson ME, Morris-Tilden CA, Senter PD. Novel peptide linkers for highly potent antibody-auristatin conjugate. Bioconjug Chem. 2008 Oct;19(10):1960-3.
| Cell experiment [1]: | |
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Cell lines |
786-O, Caki-1 and L428 cells |
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Preparation method |
The solubility of this compound in DMSO is > 36.6 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below - 20 °C for several months. |
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Reacting condition |
96 hrs |
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Applications |
In 786-O, Caki-1 and L428 cells, 1F6 mAb attached by MMAF potently inhibited cell viability, with the IC50 values of 10 ng/mL, 8 ng/mL and 123 ng/mL, respectively. |
| Animal experiment [1]: | |
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Animal models |
Mice with 786-O RCC tumor xenografts |
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Dosage form |
1 or 3 mg/kg; i.p. |
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Applications |
In mice with 786-O RCC tumor xenografts, 1F6-Val-Cit-PABC-MMAF was at least 3-fold less potent than AMAsn-(D)Lys-1F6 and AW-Met-(D)Lys-1F6. Besides, compared with AMAsn-(D)Lys-1F6 and AW-Met-(D)Lys-1F6, 1F6-Val-Cit-PABC-MMAF showed lower tolerability. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: [1]. Doronina SO, Bovee TD, Meyer DW, Miyamoto JB, Anderson ME, Morris-Tilden CA, Senter PD. Novel peptide linkers for highly potent antibody-auristatin conjugate. Bioconjug Chem. 2008 Oct;19(10):1960-3. | |
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