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| Targets |
Acetylene-linker-Val-Cit-PABC-MMAE targets the microtubule network through its MMAE payload, a potent antimitotic agent that inhibits tubulin polymerization. MMAE binds to tubulin and prevents microtubule assembly, disrupting the mitotic spindle and causing cell cycle arrest at the G2/M phase, leading to apoptosis. The Val-Cit linker is designed to be cleaved by cathepsin B, a lysosomal protease that is overexpressed in many cancer cells. The acetylene (alkyne) group enables click chemistry conjugation to azide-modified antibodies or other targeting moieties. The PABC (para-aminobenzyloxycarbonyl) spacer facilitates efficient release of the MMAE payload upon linker cleavage.
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| ln Vitro |
Acetylene-linker-Val-Cit-PABC-MMAE demonstrates potent in vitro activity as a tubulin inhibitor. The MMAE payload is a potent antimitotic agent that inhibits tubulin polymerization and disrupts microtubule dynamics. In cell-based assays, the compound shows potent cytotoxicity against cancer cell lines when released from the ADC construct. The Val-Cit linker is specifically cleaved by cathepsin B, ensuring targeted payload release in tumor cells. The compound's activity is concentration-dependent, with potent effects observed at nanomolar concentrations. The acetylene group allows for efficient conjugation to antibodies via click chemistry, enabling the construction of targeted ADCs with potent antitumor activity.
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| ln Vivo |
In vivo activity of Acetylene-linker-Val-Cit-PABC-MMAE is evaluated through studies of ADC constructs incorporating this linker-payload in animal models of human cancer. The Val-Cit linker is cleavable by cathepsin B, an enzyme that is overexpressed in tumor cells, enabling targeted release of the MMAE payload within the tumor microenvironment. In tumor-bearing mouse models, ADCs containing this linker-payload demonstrate significant antitumor efficacy. The cleavable nature of the Val-Cit linker allows for efficient payload release upon internalization into target cells. The compound's click chemistry compatibility enables conjugation to various antibodies for targeted cancer therapy. Comprehensive in vivo efficacy studies have been reported in research publications.
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| Enzyme Assay |
In vitro enzyme assays for Acetylene-linker-Val-Cit-PABC-MMAE involve characterizing the cleavage of the Val-Cit linker by cathepsin B. Recombinant cathepsin B is incubated with the linker-payload conjugate, and the release of MMAE is quantified by HPLC or LC-MS/MS. The cleavage efficiency is determined by measuring the rate of MMAE release over time. Alternatively, the compound's structure and purity can be characterized using analytical methods. High-performance liquid chromatography (HPLC) and mass spectrometry are used to verify the molecular weight (1307.62 g/mol) and chemical composition (C67H106N10O16). Purity (≥98%) is confirmed by HPLC analysis. The compound's click chemistry reactivity can be assessed by reacting with azide-containing molecules and monitoring the conjugation efficiency by HPLC or mass spectrometry.
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| Cell Assay |
In vitro cellular assays for Acetylene-linker-Val-Cit-PABC-MMAE are performed using cancer cell lines that express cathepsin B. Cells are treated with the ADC construct containing this linker-payload at varying concentrations. Cell viability is measured using MTT or CellTiter-Glo assays following 48-72 hours of treatment. IC50 values are calculated from dose-response curves. The mechanism of cell death (apoptosis vs. necrosis) is assessed using annexin V/propidium iodide staining or caspase activity assays. Cathepsin B expression levels in target cells can be confirmed by Western blot or enzymatic activity assays. Cytotoxicity is compared between cathepsin B-positive and cathepsin B-negative cell lines to confirm target specificity. The compound's ability to inhibit tubulin polymerization can be assessed using in vitro tubulin polymerization assays.
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| Animal Protocol |
In vivo animal studies for Acetylene-linker-Val-Cit-PABC-MMAE are conducted using mouse xenograft models of human cancer. Immunodeficient mice are implanted subcutaneously with cancer cells that express the target antigen and cathepsin B. Once tumors reach a predetermined size, animals are randomized into treatment groups and administered the ADC construct via intravenous injection at various doses and schedules. Tumor size is measured twice weekly using calipers, and body weight is monitored as a safety indicator. At study termination, tumors are excised, weighed, and processed for histopathological analysis. MMAE concentrations in tumor tissues can be measured by LC-MS/MS to confirm payload release. Pharmacokinetic samples are collected to determine ADC stability and exposure. Efficacy is expressed as tumor growth inhibition (TGI) relative to vehicle control.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of Acetylene-linker-Val-Cit-PABC-MMAE are characterized as part of the ADC construct. The compound has a molecular weight of 1307.62 g/mol and a molecular formula of C67H106N10O16. The Val-Cit linker is designed to be stable in circulation but cleavable by cathepsin B upon internalization into target cells. The ADC typically exhibits biphasic elimination, with an initial distribution phase followed by a slower elimination phase. The volume of distribution is generally limited to the vascular compartment due to the large molecular weight of the ADC construct. Clearance occurs primarily through proteolytic degradation. The compound is soluble in DMSO at 10 mM and should be stored at -20degC. Pharmacokinetic properties are typically assessed by size-exclusion chromatography and LC-MS/MS during ADC development.
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| Toxicity/Toxicokinetics |
Acetylene-linker-Val-Cit-PABC-MMAE is intended for laboratory research use only and has not undergone comprehensive toxicology testing. As an ADC linker-payload conjugate containing MMAE, the compound would be expected to have significant toxicity if released systemically. Standard in vitro cytotoxicity assays in cell lines are typically performed alongside efficacy studies to rule out nonspecific toxicity. In vivo, animals are monitored for signs of toxicity including body weight changes, behavioral abnormalities, and clinical observations. The Val-Cit linker is designed to be cleaved by cathepsin B, which is overexpressed in tumor cells, potentially reducing off-target toxicity. Comprehensive toxicological characterization including genotoxicity and repeated-dose toxicity studies is typically conducted as part of ADC development. The compound is not approved for human use and is strictly intended for research purposes.
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| References | |
| Additional Infomation |
Acetylene-linker-Val-Cit-PABC-MMAE (LCB14-0602) is a drug-linker conjugate consisting of the ADCs linker (Acetylene-linker-Val-Cit-PABC) and the potent tubulin inhibitor MMAE. The compound contains an alkyne group for click chemistry conjugation. The Val-Cit linker is cleavable by cathepsin B, enabling targeted payload release in tumor cells. The compound has a molecular formula of C67H106N10O16 and a molecular weight of 1307.62 g/mol. Acetylene-linker-Val-Cit-PABC-MMAE is a crucial chemical linker in ADCs for precise cancer therapy. The compound has not entered clinical trials and is available from research chemical suppliers for non-clinical research purposes only.
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| Molecular Formula |
C67H106N10O16
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|---|---|
| Molecular Weight |
1307.6160
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| Exact Mass |
1306.778
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| CAS # |
1411977-95-1
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| PubChem CID |
118986649
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| Appearance |
White to off-white solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
1312.0±65.0 °C at 760 mmHg
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| Flash Point |
747.3±34.3 °C
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| Vapour Pressure |
0.0±0.3 mmHg at 25°C
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| Index of Refraction |
1.544
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| LogP |
5.33
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| Hydrogen Bond Donor Count |
8
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| Hydrogen Bond Acceptor Count |
16
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| Rotatable Bond Count |
42
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| Heavy Atom Count |
93
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| Complexity |
2380
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| Defined Atom Stereocenter Count |
12
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| SMILES |
CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@@H]([C@@H](C)C(=O)N[C@H](C)[C@H](C2=CC=CC=C2)O)OC)OC)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N(C)C(=O)OCC3=CC=C(C=C3)NC(=O)[C@H](CCCNC(=O)N)NC(=O)[C@H](C(C)C)NC(=O)COCCOCCOCC#C
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| InChi Key |
HJNJEHBZUVWTEJ-MKXMLHHLSA-N
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| InChi Code |
InChI=1S/C67H106N10O16/c1-16-33-90-34-35-91-36-37-92-40-53(78)73-55(41(3)4)63(83)72-50(25-21-31-69-66(68)86)62(82)71-49-29-27-47(28-30-49)39-93-67(87)76(13)57(43(7)8)64(84)74-56(42(5)6)65(85)75(12)58(44(9)17-2)52(88-14)38-54(79)77-32-22-26-51(77)60(89-15)45(10)61(81)70-46(11)59(80)48-23-19-18-20-24-48/h1,18-20,23-24,27-30,41-46,50-52,55-60,80H,17,21-22,25-26,31-40H2,2-15H3,(H,70,81)(H,71,82)(H,72,83)(H,73,78)(H,74,84)(H3,68,69,86)/t44-,45+,46+,50-,51-,52+,55-,56-,57-,58-,59+,60+/m0/s1
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| Chemical Name |
[4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-3-methyl-2-[[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]acetyl]amino]butanoyl]amino]pentanoyl]amino]phenyl]methyl N-[(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]-N-methylcarbamate
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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. (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 : ~50 mg/mL (~38.24 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.25 mg/mL (0.96 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 12.5 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: ≥ 1.25 mg/mL (0.96 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 12.5 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: ≥ 1.25 mg/mL (0.96 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 | 0.7647 mL | 3.8237 mL | 7.6475 mL | |
| 5 mM | 0.1529 mL | 0.7647 mL | 1.5295 mL | |
| 10 mM | 0.0765 mL | 0.3824 mL | 0.7647 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.
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