Auristatin

Auristatin

Catalog Product Name CAS Number Molecular Formula Molecular Weight
BADC-00812 Dolastatin 15 123884-00-4 C45H68N6O9 837.06 g/mol
BADC-00029 MC-Val-Cit-PAB-MMAE 646502-53-6 C68H105N11O15 1316.63
BADC-00040 Dolastatin 10 110417-88-4 C42H68N6O6S 785.09
BADC-00026 Mc-MMAD 1401963-15-2 C51H77N7O9S 964.26
BADC-00320 MMAF Hydrochloride 1415246-68-2 C39H66ClN5O8 768.42
BADC-00032 PF-06380101 1436391-86-4 C39H62N6O6S 743.01
BADC-00318 MMAF 745017-94-1 C39H65N5O8 731.48
BADC-00188 Auristatin E 160800-57-7 C40H69N5O7 732.01
BADC-00045 Auristatin F 163768-50-1 C40H67N5O8 745.99
BADC-00309 MMAD 203849-91-6 C41H66N6O6S 771.06
BADC-00008 Val-Cit-PAB-MMAE 644981-35-1 C58H94N10O12 1123.43
BADC-00016 Vat-Cit-PAB-MMAD 1415329-13-3 C60H93N11O11S 1176.51
BADC-00635 MMAE-[d8] 2070009-72-0 C39H59D8N5O7 726.03
BADC-00617 MMAF sodium 1799706-65-2 C39H64N5NaO8 753.94
BADC-00751 DBCO-PEG4-MMAF 2360411-65-8 C68H97N7O15 1252.56
BADC-00843 D8-MMAD C41H58D8N6O6S 779.11 g/mol
BADC-00844 D8-MMAF hydrochloride C39H58D8ClN5O8 776.47 g/mol
BADC-00855 SuO-Glu-Val-Cit-PAB-MMAE 1895916-24-1 C67H103N11O17 1334.60 g/mol
BADC-00856 MMAE-SMCC 2021179-11-1 C58H89N7O14S 1140.43 g/mol
BADC-00863 DBCO-PEG4-Val-Cit-PAB-MMAF 2244602-23-9 C88H126N12O20 1672.01 g/mol

As a depsipeptide derivative of dolastoxin, auristatin could inhibit tumor growth through acting on tubulin. The activity of auristatin is higher than that of traditional chemotherapeutic drugs by 1000 times. As a linear depsipeptide natural toxic protein isolated from dolabella auricularia, dolastoxin shows strong antitumor activity by acting on tubulin. In addition to containing abundant hydroxy acids, thiophenols, D-amino acids and α-amino acids, the structure of dolastoxin also contains ethylenic and acetylenic bonds. All these groups improve the biological activity and stability of these kind of compounds.

Chemical structure

Auristatins are a series of derivatives developed by modifying the C- and N-terminal of dolastoxin-10. All structural modifications of dolastoxin-10 are designed to maintain its anticancer activity while reducing its cytotoxicity. Especially for the compounds MMAE and MMAF modified by the N-terminal and C-terminal of dolastoxin-10, they not only have good inhibitory ability for multiple tumor cells, but also show less toxicity in vivo and good pharmacokinetic characteristics. As an effective anticancer microtubule targeting agent (MTA), monomethyl auristatin E (MMAE) is a synthetic pentapeptide derived from dolastoxin-10. It introduces a 2-amino-1-phenylpropane-1-alcohol at the C-terminal and converts the N-terminal tertiary amino in the structure into secondary amino group, which can be coupled with a linker. The MMAE keep its original biological activity whose IC50 as high as 10-9-10-11 mol/L in various human cancer cell lines. Except for secondary amino coupling site, MMAF also contains a carboxyl group with larger polarity at the C- terminal, which can act as the coupling site. The introduction of carboxyl group significantly improves the ionization effect of cytotoxin part and the metabolic rate of off-target cytotoxin. It is significance to reduce the toxic and side effects of drugs by reducing the membrane permeability of off-target MMAF conjugate as well as accelerating its metabolic rate.

Mechanism of action

As a tubulin inhibitor, the anti-cancer mechanism of auristatin is to inhibit and prevent the formation of tubulin and the hydrolysis of GTP by binding to the amino acid residues of tubulin. Meanwhile, auristatin can prevent the mitosis of cancer cells, make them stagnate in the intercellular phase. Further studies indicated that auristatin could bind to the active site of genmycin/medenin exchange GTP on tubulin, resulting in cell arrest in M phase.

Application

Auristatin not only has strong growth inhibitory activities on many kinds of human hematological malignancies and solid tumor cells (eg, colon cancer, pancreatic cancer, melanoma, ovarian cancer, gastric cancer, breast cancer, lung cancer, prostate cancer and renal cell carcinoma), but also almost no drug-resistance in these cell lines. It should be noted, auristatin also show good pharmacokinetic properties in vivo studies. The Food and Drug Administration (FDA) approved auristatin-based antibody drug conjugates (ADCs), followed by Adcetris®, recently Polivy® became 2nd approved ADC in 2019. Adcetris®, is an anti-CD30 ADC comprising a cleavable linker by proteases, such as cathepsin B and monomethyl auristatin (MMAE) as a payload with an average drug-to-antibody ratio (DAR) of 4. Polivy® is an anti-CD79b ADC comprising the same linker and payload as Adcetris® with DAR of 3.5. In addition, including our ADCs, enfortumab vedotin, over 10 ADCs with auristatins such as MMAE or monomethyl auristatin F (MMAF) as payload are currently in clinical trials, which account for half of all ADCs in clinical trials at present.

References

  1. Best, R.L.; et al. Microtubule and tubulin binding and regulation of microtubule dynamics by the antibody drug conjugate (ADC) payload, monomethyl auristatin E (MMAE): Mechanistic insights into MMAE ADC peripheral neuropathy. Toxicology and Applied Pharmacology, 2021, 421: 115534.
  2. Mendelsohn, B.A.; et al. Investigation of hydrophilic auristatin derivatives for use in antibody drug conjugates. Bioconjugate Chem., 2017, 28: 371−381.
* Only for research. Not suitable for any diagnostic or therapeutic use.

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