Name: MC-Val-Cit-PAB-Auristatin E
Brand: BOC Sciences
Rating: 5 (1 reviews)

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Synonyms

MC Val Cit PAB Auristatin E

IUPAC Name

[4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-2-[6-(2,5-dioxopyrrol-1-yl)hexanoylamino]-3-methylbutanoyl]amino]pentanoyl]amino]phenyl]methyl-[(2S)-1-[[(2S)-1-[[(3R,4S,5S)-1-[(2S)-2-[(1R,2R)-3-[[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-dimethylazanium

Canonical SMILES

O[C@@H](C1=CC=CC=C1)[C@@H](C)NC([C@H](C)[C@H]([C@@]2([H])N(CCC2)C(C[C@@H](OC)[C@@]([C@@H](C)CC)([H])N(C)C([C@H](C(C)C)NC([C@H](C(C)C)[N+](C)(C)CC3=CC=C(NC([C@H](CCCNC(N)=O)NC([C@H](C(C)C)NC(CCCCCN4C(C=CC4=O)=O)=O)=O)=O)C=C3)=O)=O)=O)OC)=O

InChI

InChI=1S/C68H107N11O13/c1-16-44(8)59(52(91-14)39-56(83)77-38-24-28-51(77)62(92-15)45(9)63(85)71-46(10)61(84)48-25-19-17-20-26-48)76(11)67(89)58(42(4)5)75-66(88)60(43(6)7)79(12,13)40-47-30-32-49(33-31-47)72-64(86)50(27-23-36-70-68(69)90)73-65(87)57(41(2)3)74-53(80)29-21-18-22-37-78-54(81)34-35-55(78)82/h17,19-20,25-26,30-35,41-46,50-52,57-62,84H,16,18,21-24,27-29,36-40H2,1-15H3,(H7-,69,70,71,72,73,74,75,80,85,86,87,88,90)/p+1/t44-,45+,46+,50-,51-,52+,57-,58-,59-,60-,61+,62+/m0/s1

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MC-Val-Cit-PAB-Auristatin E is a conjugate designed for targeted cancer therapy, combining the potent cytotoxic agent Auristatin E with a targeting peptide and a linker system. Auristatin E, a derivative of the potent anti-tumor drug monomethyl auristatin E (MMAE), disrupts microtubule dynamics, leading to cell cycle arrest and apoptosis in rapidly dividing cancer cells. The conjugation of Auristatin E to a peptide through the MC-Val-Cit-PAB linker ensures precise delivery of the cytotoxic payload to the tumor site, minimizing damage to healthy tissues and enhancing therapeutic efficacy.

One of the key applications of MC-Val-Cit-PAB-Auristatin E is in antibody-drug conjugates (ADCs) for targeted cancer therapy. The conjugate consists of a linker that connects Auristatin E to a peptide, which is capable of binding to specific cancer cell surface markers. This specificity allows the cytotoxic drug to be delivered directly to the tumor site, reducing off-target toxicity and enhancing the overall therapeutic index of the drug. By selectively targeting cancer cells, MC-Val-Cit-PAB-Auristatin E increases the localized concentration of the drug, improving its effectiveness while minimizing side effects often associated with conventional chemotherapy.

In addition to its role in ADCs, MC-Val-Cit-PAB-Auristatin E is also explored for its potential in overcoming drug resistance mechanisms in cancer therapy. Many cancers develop resistance to traditional chemotherapeutic agents, including those targeting the microtubule network. By using a targeted delivery system, MC-Val-Cit-PAB-Auristatin E can bypass some of the resistance mechanisms commonly seen in cancer cells. The linker system can help ensure that the cytotoxic drug is specifically delivered to tumor cells, improving treatment outcomes even in resistant cancer strains.

MC-Val-Cit-PAB-Auristatin E also plays a critical role in optimizing the pharmacokinetics of its payload. Traditional chemotherapeutic agents like Auristatin E can have poor solubility, limited bioavailability, and short half-lives in the body. The MC-Val-Cit-PAB linker improves the stability and solubility of Auristatin E, facilitating its controlled release at the target site. This controlled release helps to enhance the drug’s bioavailability and reduce systemic exposure, which is crucial for achieving a more effective and less toxic treatment regimen.

1.Targeted drug delivery through the traceless release of tertiary and heteroaryl amines from antibody-drug conjugates

Staben LR, et al.

The reversible attachment of a small-molecule drug to a carrier for targeted delivery can improve pharmacokinetics and the therapeutic index. Previous studies have reported the delivery of molecules that contain primary and secondary amines via an amide or carbamate bond; however, the ability to employ tertiary-amine-containing bioactive molecules has been elusive. Here we describe a bioreversible linkage based on a quaternary ammonium that can be used to connect a broad array of tertiary and heteroaryl amines to a carrier protein. Using a concise, protecting-group-free synthesis we demonstrate the chemoselective modification of 12 complex molecules that contain a range of reactive functional groups. We also show the utility of this connection with both protease-cleavable and reductively cleavable antibody-drug conjugates that were effective and stable in vitro and in vivo. Studies with a tertiary-amine-containing antibiotic show that the resulting antibody-antibiotic conjugate provided appropriate stability and release characteristics and led to an unexpected improvement in activity over the conjugates previously connected via a carbamate.