| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| Other Sizes |
| Targets |
The primary molecular target of Val-Cit-amide-Cbz-N(Me)-Maytansine, when used as an ADC, is the hepatocyte growth factor receptor c-Met (MET). c-Met is a receptor tyrosine kinase overexpressed in various human cancers (lung, breast, gastric, colon) and associated with poor prognosis and metastasis. The ADC binds specifically to c-Met on the cancer cell surface, is internalized, and the Val-Cit linker is cleaved by lysosomal proteases (cathepsin B), releasing the maytansine payload. The ultimate target of released maytansine is tubulin, where it inhibits microtubule assembly, leading to cell cycle arrest and apoptosis.
|
|---|---|
| ln Vitro |
In vitro, the activity of Val-Cit-amide-Cbz-N(Me)-Maytansine is evaluated as part of an ADC construct. For a c-Met-targeting ADC, it shows potent cytotoxicity against high c-Met-expressing cells (e.g., MKN45 gastric cancer cells) with IC₅0 in the sub-nanomolar to low nanomolar range. Cytotoxicity is specific and can be blocked by competition with excess unconjugated anti-c-Met antibody. The Val-Cit linker is stable in plasma but efficiently cleaved in lysosomes, as confirmed by LC-MS/MS analysis of released payload. The compound itself, as a payload-linker, is toxic to cells in a non-specific manner if not conjugated to a targeting antibody, and serves as a model for ADC drug discovery.
|
| Enzyme Assay |
A typical non-cellular binding assay for the c-Met-targeting antibody or ADC is surface plasmon resonance (SPR). Recombinant human c-Met protein is immobilized on a sensor chip. The ADC is injected at 0.1-100 nM over the surface. Association and dissociation rate constants are measured, and KD is calculated (typically picomolar range, e.g., 50-500 pM). For the maytansine payload, a tubulin polymerization assay is performed: purified tubulin (2 mg/mL) in buffer (80 mM PIPES pH 6.9, 2 mM MgCl2, 0.5 mM EGTA, 1 mM GTP) is pre-incubated with varying payload concentrations (0.01-10 uM) at 37degC. Polymerization is monitored by increase in optical density at 340 nm for 30 min. IC₅0 is calculated.
|
| Cell Assay |
A standard in vitro cell-based assay for an anti-c-Met ADC uses c-Met-positive gastric cancer MKN45 cells. Cells are cultured in RPMI-1640 with 10% FBS at 37degC, 5% CO2. For cytotoxicity, cells are seeded in 96-well plates at 3 × 103 cells/well. Serial dilutions of ADC (0.001-100 nM) are added. After 96 h, cell viability is measured by CellTiter-Glo. IC₅0 is calculated. To confirm target-specific killing, a competition assay pre-incubates cells with 10-fold excess unconjugated anti-c-Met antibody for 1 h before adding ADC. An isotype control ADC serves as negative control. Internalization is assessed by incubating cells with ADC (10 nM) at 37degC for 1-24 h, then staining with anti-human secondary antibody and analyzing by flow cytometry or confocal microscopy.
|
| Animal Protocol |
An in vivo animal study for an anti-c-Met ADC containing this payload is performed in a subcutaneous xenograft model. Female BALB/c nude mice (6-8 weeks) are injected subcutaneously with 5 × 10⁶ MKN45 cells in 0.1 mL PBS. When tumors reach 150-200 mm3, mice are randomized (n=8-10). ADC is formulated in 10 mM histidine buffer (pH 5.5) with 5% trehalose and 0.01% Tween-80, and administered intravenously at 1, 3, 10, 30 mg/kg once weekly for 3 weeks. Control receives vehicle. Tumor volumes are measured twice weekly. Body weight is monitored. At study end (day 21), tumors are excised, weighed, and analyzed by IHC for Ki-67 and TUNEL. Plasma is collected for PK analysis and measurement of ADC and released payload. All procedures require IACUC approval.
|
| ADME/Pharmacokinetics |
The pharmacokinetic (PK) properties of the payload-linker alone are not reported, as it is not administered as a standalone therapeutic. When conjugated to an antibody, the ADC PK is dominated by the antibody: long terminal half-life (days), low clearance, low volume of distribution. The ADC is stable in circulation with minimal deconjugation. The released maytansine payload is rapidly cleared from plasma, minimizing systemic toxicity. The linker is designed for stability in plasma and cleavage in lysosomes. Detailed PK parameters for similar ADCs can be found in literature.
|
| Toxicity/Toxicokinetics |
No toxicity data is available for the payload alone. The toxicity of an anti-c-Met ADC is evaluated in rats and cynomolgus monkeys. Main toxicities are related to the maytansine payload (bone marrow suppression, neutropenia, thrombocytopenia, gastrointestinal effects) and on-target c-Met expression in normal tissues. The MTD and therapeutic index are determined in preclinical studies. For research use only; not for human therapeutic use.
|
| References | |
| Additional Infomation |
Val-Cit-amide-Cbz-N(Me)-Maytansine is not an approved drug. It is a research-grade ADC payload-linker used for developing ADCs and bispecific antibodies targeting c-Met. Its mechanism involves targeted delivery of maytansine to c-Met-expressing cancer cells, followed by cathepsin-mediated linker cleavage and payload release, leading to microtubule disruption and cell death. It is a valuable tool for targeted cancer therapy research. No clinical trials have been registered for this specific payload-linker. For research use only; not for diagnostic or therapeutic applications.
|
| Exact Mass |
1139.531
|
|---|---|
| CAS # |
1628543-59-8
|
| PubChem CID |
118700538
|
| Appearance |
White to off-white solid powder
|
| Hydrogen Bond Donor Count |
7
|
| Hydrogen Bond Acceptor Count |
16
|
| Rotatable Bond Count |
21
|
| Heavy Atom Count |
80
|
| Complexity |
2250
|
| Defined Atom Stereocenter Count |
10
|
| SMILES |
C[C@@H]1[C@@H]2C[C@]([C@@H](/C=C/C=C(/CC3=CC(=C(C(=C3)OC)Cl)N(C(=O)C[C@@H]([C@]4([C@H]1O4)C)OC(=O)[C@H](C)N(C)C(=O)CCN(C)C(=O)OCC5=CC=C(C=C5)NC(=O)[C@H](CCCNC(=O)N)NC(=O)[C@H](C(C)C)N)C)\\C)OC)(NC(=O)O2)O
|
| InChi Key |
WHRVZTYLCHEVBV-HIIFFYOTSA-N
|
| InChi Code |
InChI=1S/C55H78ClN9O15/c1-30(2)46(57)49(69)61-37(15-13-22-59-51(58)71)48(68)60-36-19-17-34(18-20-36)29-77-53(73)63(7)23-21-43(66)64(8)33(5)50(70)79-42-27-44(67)65(9)38-25-35(26-39(75-10)45(38)56)24-31(3)14-12-16-41(76-11)55(74)28-40(78-52(72)62-55)32(4)47-54(42,6)80-47/h12,14,16-20,25-26,30,32-33,37,40-42,46-47,74H,13,15,21-24,27-29,57H2,1-11H3,(H,60,68)(H,61,69)(H,62,72)(H3,58,59,71)/b16-12+,31-14+/t32-,33+,37+,40+,41-,42+,46+,47+,54+,55+/m1/s1
|
| Chemical Name |
[(1S,2R,3S,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] (2S)-2-[3-[[4-[[(2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-5-(carbamoylamino)pentanoyl]amino]phenyl]methoxycarbonyl-methylamino]propanoyl-methylamino]propanoate
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO: 100 mg/mL (87.66 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (2.19 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 25.0 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: ≥ 2.5 mg/mL (2.19 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 25.0 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: ≥ 2.5 mg/mL (2.19 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
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
Copyright 2020 InvivoChem LLC | All Rights Reserved
