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Purity: ≥98%
Lys-SMCC-DM1 is the active metabolite of T-DM1. T-DM1 is an FDA approved HER2-targeting ADC (antibody-drug conjugate). Lys-SMCC-DM1 (also known as Lys-Nε-MCC-DM1) is a drug-linker conjugate in which DM1 acts as an inhibitor of tubulin polymerization. T-DM1 is a human epidermal growth factor receptor 2 (HER2)-targeting ADC for cancer treatment.
| Targets |
Maytansinoids
Lys-SMCC-DM1 is the linker-payload component (active metabolite) released from the antibody-drug conjugate T-DM1 (trastuzumab emtansine). It functions as a tubulin polymerization inhibitor.[1] |
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| ln Vitro |
Lys-SMCC-DM1 have a minimal permeability level [1].
In KPL-4 and MDA-MB-468 cells, Lys-SMCC-DM1 exhibits cytotoxicity with IC50 values of 24.8 nM and 40.5 nM, respectively[2]. In MDCKII/SLC46A3 dC cells, Lys-SMCC-DM1 (200 μM) inhibits the uptake of estrone 3-sulfate by SLC46A3[2]. The cytotoxic activity of the free payload Lys-SMCC-DM1 was evaluated. The IC50 value for inhibiting the growth of HER2-positive KPL-4 breast cancer cells was 24.8 nM. The IC50 value for inhibiting the growth of HER2-negative MDA-MB-468 breast cancer cells was 40.5 nM. [1] In a co-culture assay with HER2-positive KPL-4 cells and HER2-negative MDA-MB-468 cells, the parent ADC T-DM1 (which releases Lys-SMCC-DM1 intracellularly) selectively killed only the HER2-positive KPL-4 cells. It did not kill the adjacent HER2-negative MDA-MB-468 cells, indicating a lack of bystander killing effect under these conditions. [1] The membrane permeability of Lys-SMCC-DM1 was characterized as low. Its distribution coefficient (Log D at pH 7.4) was 0.2. Its effective permeability coefficient (Peff) in a parallel artificial membrane permeability assay (PAMPA) was <0.1 x 10^-6 cm/s at both pH 5.0 and pH 7.4. [1] |
| Cell Assay |
Cell Growth Inhibition Assay: Cells (KPL-4 or MDA-MB-468) were seeded in 96-well plates at densities of 1000 or 2000 cells per well, respectively. After overnight incubation, serially diluted solutions of the test compound (Lys-SMCC-DM1) were added. Following a 5-day incubation period, cell viability was assessed using a luminescent cell viability assay based on ATP quantification. The luminescence signal, proportional to the number of viable cells, was measured. Dose-response curves were generated, and IC50 values (concentration causing 50% inhibition of cell growth) were determined using a sigmoid Emax model. [1]
Co-culture Bystander Killing Assay: HER2-positive KPL-4 cells and HER2-negative MDA-MB-468 cells were mixed and seeded together in a 6-well plate (1x10^5 KPL-4 cells and 3x10^5 MDA-MB-468 cells per well in 2 mL medium). After overnight incubation, the parent ADC T-DM1 (which releases Lys-SMCC-DM1 upon internalization) was added to the culture. After 5 days of treatment, all viable (adherent) cells were collected. The total number of viable cells per well was determined using an automated cell counter. To distinguish between the two cell types within the mixed population, the cells were stained with a fluorescently-labeled (FITC) anti-HER2 antibody and incubated on ice. After washing, the fluorescence signal of the stained cells was analyzed by flow cytometry. Based on the total cell count and the percentage of HER2-positive and HER2-negative populations determined by flow cytometry, the absolute numbers of surviving KPL-4 and MDA-MB-468 cells in each treatment well were calculated. [1] |
| References |
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| Additional Infomation |
Lys-SMCC-DM1 is the cytotoxic payload linked to the antibody in the FDA-approved antibody-drug conjugate (ADC) T-DM1 (trastuzumab-mettansine) for the treatment of HER2-positive breast cancer. [1] After T-DM1 is endocytosed and processed intracellularly by target cells, Lys-SMCC-DM1 is released into the target cells. The linker in T-DM1 is described as “uncleavable,” while Lys-SMCC-DM1 represents an active metabolite containing a linker linked to the DM1 toxin. [1] This study highlights that the low membrane permeability of Lys-SMCC-DM1 (Log D = 0.2, Peff < 0.1) is a key factor contributing to the lack of bystander killing effect of T-DM1, in stark contrast to the high-permeability payload DS-8201a. This limits its ability to kill adjacent antigen-negative cancer cells in HER2-expressing heterogeneous tumors. [1]
According to reports, the molecular weight of Lys-SMCC-DM1 is 1103.7 g/mol. [1] |
| Molecular Formula |
C₅₃H₇₅CLN₆O₁₅S.CF3COOH
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|---|---|
| Molecular Weight |
1217.73
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| Exact Mass |
1102.47
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| CAS # |
1281816-04-3
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| Related CAS # |
(Rac)-Lys-SMCC-DM1
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| PubChem CID |
71587969
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| Appearance |
White to off-white solid powder
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| LogP |
5.693
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
17
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| Rotatable Bond Count |
19
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| Heavy Atom Count |
76
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| Complexity |
2200
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| Defined Atom Stereocenter Count |
9
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| 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)CCSC5CC(=O)N(C5=O)CC6CCC(CC6)C(=O)NCCCC[C@@H](C(=O)O)N)C)\C)OC)(NC(=O)O2)O
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| InChi Key |
UBRZDBDIKWWPEN-ANAFPORDSA-N
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| InChi Code |
InChI=1S/C53H75ClN6O15S/c1-29-12-11-14-40(72-8)53(70)27-38(73-51(69)57-53)30(2)46-52(4,75-46)41(26-43(62)59(6)36-23-33(22-29)24-37(71-7)45(36)54)74-50(68)31(3)58(5)42(61)19-21-76-39-25-44(63)60(48(39)65)28-32-15-17-34(18-16-32)47(64)56-20-10-9-13-35(55)49(66)67/h11-12,14,23-24,30-32,34-35,38-41,46,70H,9-10,13,15-22,25-28,55H2,1-8H3,(H,56,64)(H,57,69)(H,66,67)/b14-11+,29-12+/t30-,31+,32?,34?,35+,38+,39+,40-,41+,46+,52+,53+/m1/s1
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| Chemical Name |
(2S)-2-amino-6-[[4-[[(3S)-3-[3-[[(2S)-1-[[(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]oxy]-1-oxopropan-2-yl]-methylamino]-3-oxopropyl]sulfanyl-2,5-dioxopyrrolidin-1-yl]methyl]cyclohexanecarbonyl]amino]hexanoic acid
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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: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| 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 : ~100 mg/mL (~90.60 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (2.27 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 (2.27 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 (2.27 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 10% DMSO+ 40% PEG300+ 5% Tween-80+ 45% saline: ≥ 2.5 mg/mL (2.27 mM) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.8212 mL | 4.1060 mL | 8.2120 mL | |
| 5 mM | 0.1642 mL | 0.8212 mL | 1.6424 mL | |
| 10 mM | 0.0821 mL | 0.4106 mL | 0.8212 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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