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| 2mg |
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| 5mg |
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| Targets |
The primary molecular target of MC-Val-Cit-PAB-Auristatin E is tubulin, the protein that forms microtubules, which are essential for cell division. Auristatin E, the cytotoxic payload, binds to tubulin and inhibits its polymerization, disrupting the mitotic spindle and causing cell cycle arrest at the G2/M phase. This leads to apoptosis of the target cells. The MC-Val-Cit-PAB linker targets the lysosomal protease cathepsin B, which cleaves the linker to release the active Auristatin E within the target cell. The compound is designed for use in ADCs, where the antibody targets a tumor-associated antigen, delivering the cytotoxic payload specifically to cancer cells.
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| ln Vitro |
In vitro studies demonstrate that MC-Val-Cit-PAB-Auristatin E has potent antitumor activity. The compound is a drug-linker conjugate that can be incorporated into ADCs. When the ADC binds to its target antigen on the surface of cancer cells, it is internalized via receptor-mediated endocytosis. The ADC is trafficked to the lysosome, where the MC-Val-Cit-PAB linker is cleaved by lysosomal proteases (e.g., cathepsin B), releasing the active Auristatin E. The released Auristatin E inhibits tubulin polymerization, causing cell cycle arrest and apoptosis. The compound demonstrates significant antitumor activity in various cancer cell lines.
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| ln Vivo |
In vivo studies of MC-Val-Cit-PAB-Auristatin E are conducted in the context of complete ADC molecules incorporating this drug-linker conjugate. ADCs containing MC-Val-Cit-PAB-Auristatin E have been evaluated in various animal models of cancer. In xenograft models, these ADCs demonstrate significant tumor growth inhibition and, in some cases, tumor regression. The compounds are typically administered via intravenous injection at doses determined from pharmacokinetic and toxicology studies. Pharmacodynamic endpoints include measurement of tumor growth inhibition, assessment of apoptosis and cell cycle markers in tumor tissues, and evaluation of safety and tolerability. The bioreversible linkage ensures that the ADC is stable in circulation but releases the payload within target cells.
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| Enzyme Assay |
For ADC synthesis, MC-Val-Cit-PAB-Auristatin E is conjugated to a monoclonal antibody via the maleimide group on the MC (maleimidocaproyl) moiety. The antibody is first reduced to generate free thiol groups, which react with the maleimide to form a stable thioether linkage. The conjugation reaction is typically performed in PBS buffer at pH 6.5-7.4 at room temperature or 4°C. The ADC is purified by size exclusion chromatography or tangential flow filtration and characterized by UV-Vis spectroscopy, HPLC, and mass spectrometry. The drug-to-antibody ratio (DAR) is determined by HPLC or mass spectrometry.
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| Cell Assay |
For cellular studies, cancer cells expressing the target antigen are cultured in appropriate medium with 10% FBS and antibiotics. Cells are seeded in 96-well plates and treated with ADCs containing MC-Val-Cit-PAB-Auristatin E at varying concentrations (0.001-100 µg/ml) for 48-96 hours. Cell viability is assessed by MTT or CellTiter-Glo assays. IC50 values are calculated from dose-response curves. For mechanistic studies, cells are analyzed for cell cycle distribution by flow cytometry, apoptosis by Annexin V/PI staining, and tubulin polymerization by immunofluorescence. Target antigen expression is confirmed by flow cytometry or Western blot.
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| Animal Protocol |
For in vivo efficacy studies, 6-8 week old female immunodeficient mice (e.g., nude or SCID) are used. Mice are subcutaneously implanted with cancer cells expressing the target antigen in the flank. When tumors reach approximately 100-200 mm³, animals are randomized into treatment groups (n = 6-10 per group). ADCs containing MC-Val-Cit-PAB-Auristatin E are formulated in vehicle (e.g., PBS or histidine buffer) and administered intravenously at doses of 1-30 mg/kg, typically on a q4d × 4 or q7d × 3 schedule. Tumor volumes are measured twice weekly using calipers. Body weights are monitored for toxicity. At study termination, tumors are excised and processed for histopathological examination, apoptosis assessment (TUNEL), and biomarker analysis. Blood samples may be collected for pharmacokinetic analysis.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of MC-Val-Cit-PAB-Auristatin E are studied as part of the complete ADC molecule. The ADC exhibits a typical biphasic pharmacokinetic profile with an initial distribution phase followed by a slower elimination phase. The half-life of the ADC depends on the antibody and the linker stability. The MC-Val-Cit-PAB linker is designed to be stable in circulation, preventing premature release of the payload. The released Auristatin E is metabolized and cleared. The pharmacokinetic properties support the use of ADCs containing this linker in cancer therapy.
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| Toxicity/Toxicokinetics |
Toxicological data for MC-Val-Cit-PAB-Auristatin E are derived from toxicology studies of ADCs containing this drug-linker conjugate. The toxicity of the ADC is primarily attributed to the payload (Auristatin E) and the pharmacology of target engagement. Common toxicities include myelosuppression, gastrointestinal effects, and hepatotoxicity. The safety and tolerability of ADCs containing this conjugate are evaluated in animal toxicology studies. Parameters assessed include clinical observations, body weight, food consumption, clinical pathology, organ weights, and histopathology. The MC-Val-Cit-PAB linker is designed to be stable in circulation, reducing off-target toxicity.
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| References | |
| Additional Infomation |
MC-Val-Cit-PAB-Auristatin E (CAS 2055896-77-8) is an ADC linker compound with Auristatin E, a potent cytotoxic tubulin modifier. It is a drug-linker conjugate for ADC with potent antitumor activity. The compound is a bioreversible linkage used for synthesis of effective and stable ADCs. Auristatin E inhibits tubulin polymerization, causing cell cycle arrest and apoptosis. The MC-Val-Cit-PAB linker is cleaved by lysosomal proteases to release the payload. The compound is strictly for research use only.
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| Molecular Formula |
C68H108N11O13
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|---|---|
| Molecular Weight |
1287.65103816986
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| Exact Mass |
1286.812
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| CAS # |
2055896-77-8
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| PubChem CID |
139035077
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| Appearance |
White to off-white solid powder
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| LogP |
5
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| Hydrogen Bond Donor Count |
8
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| Hydrogen Bond Acceptor Count |
13
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| Rotatable Bond Count |
38
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| Heavy Atom Count |
92
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| Complexity |
2440
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| Defined Atom Stereocenter Count |
12
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| SMILES |
[C@@H]([C@]1([H])CCCN1C(=O)C[C@@H](OC)[C@]([H])([C@@H](C)CC)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)[N+](C)(C)CC1C=CC(NC(=O)[C@H](CCCNC(=O)N)NC(=O)[C@H](C(C)C)NC(=O)CCCCCN2C(C=CC2=O)=O)=CC=1)(OC)[C@@H](C)C(=O)N[C@H](C)[C@H](C1C=CC=CC=1)O
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| InChi Key |
ULBSEZSVDXRNQN-UIMDRQLBSA-O
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| InChi Code |
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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| Chemical 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
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: (1). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. (2). This product is not stable in solution, please use freshly prepared working solution for optimal results. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~200 mg/mL (~155.32 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5 mg/mL (3.88 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 5 mg/mL (3.88 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 5 mg/mL (3.88 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.7766 mL | 3.8830 mL | 7.7661 mL | |
| 5 mM | 0.1553 mL | 0.7766 mL | 1.5532 mL | |
| 10 mM | 0.0777 mL | 0.3883 mL | 0.7766 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Products are for research use only; We do not sell to patients
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