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Purity: =98.34%
Deruxtecan (DS-8201a; DS8201a; exatecan analog; DX-8951 analog), a drug-linker conjugate for antibody-drug conjugate (ADC, Patritumab deruxtecan or U3-1402), is a novel, potent toxin and linker moiety of DS-8201. Antibody-drug conjugates deliver anticancer agents selectively and efficiently to tumor tissue and have significant antitumor efficacy with a wide therapeutic window. DS-8201a is a human epidermal growth factor receptor 2 (HER2)-targeting antibody-drug conjugate prepared using a novel linker-payload system with a potent topoisomerase I inhibitor, exatecan derivative (DX-8951 derivative, DXd). It was effective against trastuzumab emtansine (T-DM1)-insensitive patient-derived xenograft models with both high and low HER2 expression. In this study, the bystander killing effect of DS-8201a was evaluated and compared with that of T-DM1. We confirmed that the payload of DS-8201a, DXd (1), was highly membrane-permeable whereas that of T-DM1, Lys-SMCC-DM1, had a low level of permeability. Under a coculture condition of HER2-positive KPL-4 cells and negative MDA-MB-468 cells in vitro, DS-8201a killed both cells, whereas T-DM1 and an antibody-drug conjugate with a low permeable payload, anti-HER2-DXd (2), did not. In vivo evaluation was carried out using mice inoculated with a mixture of HER2-positive NCI-N87 cells and HER2-negative MDA-MB-468-Luc cells by using an in vivo imaging system. In vivo, DS-8201a reduced the luciferase signal of the mice, indicating suppression of the MDA-MB-468-Luc population; however, T-DM1 and anti-HER2-DXd (2) did not. Furthermore, it was confirmed that DS-8201a was not effective against MDA-MB-468-Luc tumors inoculated at the opposite side of the NCI-N87 tumor, suggesting that the bystander killing effect of DS-8201a is observed only in cells neighboring HER2-positive cells, indicating low concern in terms of systemic toxicity. These results indicated that DS-8201a has a potent bystander effect due to a highly membrane-permeable payload and is beneficial in treating tumors with HER2 heterogeneity that are unresponsive to T-DM1.
| Targets |
Camptothecins; TOP I; topoisomerase I
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| ln Vitro |
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| ln Vivo |
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| Enzyme Assay |
Parallel artificial membrane permeability assay (PAMPA) was carried out using a Freedom EVO200 system (Tecan, Männedorf, Switzerland). The filter membrane of the acceptor plate (Stirwell PAMPA Sandwich; Pion, Billerica, MA, USA) was coated with GIT‐0 lipid solution (Pion). Each compound solution in DMSO (10 mM) was added to Prisma HT buffer (Pion) to obtain 5‐μM donor solutions (containing 0.05% DMSO, pH 5.0 and pH 7.4), and then placed on a donor plate. The acceptor plate was filled with an acceptor sink buffer (Pion). The donor plate was stacked onto the acceptor plate and incubated for 4 h at 25°C. After incubation, the concentrations of compounds in both plates were measured by an LC‐MS/MS system (API 4000). The permeability coefficient (Peff; 10−6 cm/s) was calculated using PAMPA Evolution DP software (Pion).[1]
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| Cell Assay |
Cells were seeded in a 96‐well plate at 1000 cells/well for KPL‐4 and 2000 cells/well for MDA‐MB‐468. After overnight incubation, a serially diluted solution of each ADC was added. Cell viability was evaluated after 5 days using a CellTiter‐Glo luminescent cell viability assay from Promega (Madison, WI, USA) according to the manufacturer's instructions. For coculture study, KPL‐4 and MDA‐MB‐468 cells were seeded in a 6‐well plate at 1 × 105 cells and 3 × 105 cells, respectively, in 2 mL/well culture medium. After overnight incubation, the supernatant was removed from the plate and each ADC diluent (10 nM) was added at 6 mL/well. Viable cells were detached from the plate after 5 days of culture, and the cell number in each well was determined using a cell counter. In order to determine the ratio of KPL‐4 and MDA‐MD‐468 cells of the total viable cells, the cells were stained with anti‐HER2/nue FITC (Becton, Dickinson and Company, Franklin Lakes, NJ, USA) and incubated on ice for 20 min. After washing, fluorescent signals of 2 × 104 stained cells were measured using a flow cytometer. Based on the number and ratio of HER2‐positive and HER2‐negative cells in each treatment well, the number of KPL‐4 or MDA‐MB‐468 cells was calculated.[1]
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| Animal Protocol |
In vivo xenograft studies
All in vivo studies were carried out in accordance with the local guidelines of the Institutional Animal Care and Use Committee. Specific pathogen‐free female CAnN.Cg‐Foxn1nu/CrlCrlj mice (BALB/c nude mice) aged 5 weeks were purchased from Charles River Laboratories Japan Inc. (Yokohama, Japan) All models were established by s.c. inoculation in the flanks of the mice. NCI‐N87 and MDA‐MB‐468‐Luc models were established by injecting 5 × 106 and 1 × 107 cells suspended in a Matrigel matrix, respectively. After 6 days for NCI‐N87, and 9 days for MDA‐MB‐468‐Luc models, the tumor‐bearing mice were randomized into treatment and control groups based on the tumor volume, and dosing initiated (day 0). Each ADC was given i.v. to the mice at a dose of 3 or 10 mg/kg, and a volume of 10 mL/kg. As a vehicle, ABS buffer (10 mM acetate buffer, 5% sorbitol, pH 5.5) was given at the same volume as the ADCs. The tumor volume was defined as 1/2 × length × width2.[1] In vivo luciferase imaging Seven days after inoculating the mixture of 5 × 106 NCI‐N87 cells and 1 × 107 MDA‐MB‐468‐Luc cells suspended in the Matrigel matrix into the right flank of the mice at a total volume of 100 μL, the tumor‐bearing mice were randomized into treatment and control groups based on the tumor volume, and dosing initiated (day 0). Each ADC or the vehicle was given i.v. to the mice. Luciferase activity of each mouse was measured using an in vivo imaging system (IVIS 200 Imaging System; PerkinElmer Waltham, MA, USA) twice a week in parallel with the measurement of tumor length 10 min after administering 150 mg/kg luciferin i.v. The amount of luminescence was analyzed using analysis software as average radiance (p/s/cm2/sr). For another study, MDA‐MB‐468‐Luc cells at a density of 1.5 × 107 cells were inoculated into the left flank of the mice in addition to the inoculation of the mixture into the right flank. Seven days after inoculation, dosing and evaluation were undertaken in a similar manner as described above.[1] |
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| References | ||
| Additional Infomation |
Antibody-drug conjugates deliver anticancer agents selectively and efficiently to tumor tissue and have significant antitumor efficacy with a wide therapeutic window. DS-8201a is a human epidermal growth factor receptor 2 (HER2)-targeting antibody-drug conjugate prepared using a novel linker-payload system with a potent topoisomerase I inhibitor, exatecan derivative (DX-8951 derivative, DXd). It was effective against trastuzumab emtansine (T-DM1)-insensitive patient-derived xenograft models with both high and low HER2 expression. In this study, the bystander killing effect of DS-8201a was evaluated and compared with that of T-DM1. We confirmed that the payload of DS-8201a, DXd (1), was highly membrane-permeable whereas that of T-DM1, Lys-SMCC-DM1, had a low level of permeability. Under a coculture condition of HER2-positive KPL-4 cells and negative MDA-MB-468 cells in vitro, DS-8201a killed both cells, whereas T-DM1 and an antibody-drug conjugate with a low permeable payload, anti-HER2-DXd (2), did not. In vivo evaluation was carried out using mice inoculated with a mixture of HER2-positive NCI-N87 cells and HER2-negative MDA-MB-468-Luc cells by using an in vivo imaging system. In vivo, DS-8201a reduced the luciferase signal of the mice, indicating suppression of the MDA-MB-468-Luc population; however, T-DM1 and anti-HER2-DXd (2) did not. Furthermore, it was confirmed that DS-8201a was not effective against MDA-MB-468-Luc tumors inoculated at the opposite side of the NCI-N87 tumor, suggesting that the bystander killing effect of DS-8201a is observed only in cells neighboring HER2-positive cells, indicating low concern in terms of systemic toxicity. These results indicated that DS-8201a has a potent bystander effect due to a highly membrane-permeable payload and is beneficial in treating tumors with HER2 heterogeneity that are unresponsive to T-DM1.[1]
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| Molecular Formula |
C52H56FN9O13
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|---|---|
| Molecular Weight |
1034.05195617676
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| Exact Mass |
1,033.40
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| Elemental Analysis |
C, 60.40; H, 5.46; F, 1.84; N, 12.19; O, 20.11
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| CAS # |
1599440-13-7
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| Related CAS # |
Exatecan mesylate;169869-90-3;Deruxtecan-d6;2760715-89-5;Deruxtecan-d5;Exatecan mesylate dihydrate;197720-53-9
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| PubChem CID |
118305111
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| Appearance |
White to yellow solid powder
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| Density |
1.48±0.1 g/cm3
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| Boiling Point |
1491.1±65.0 °C
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| LogP |
-0.4
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| Hydrogen Bond Donor Count |
7
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| Hydrogen Bond Acceptor Count |
15
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| Rotatable Bond Count |
22
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| Heavy Atom Count |
75
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| Complexity |
2360
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| Defined Atom Stereocenter Count |
3
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| SMILES |
FC1=CC2=C3C(=C1C)CC[C@@H](C3=C1C(C3=CC4[C@](C(=O)OCC=4C(N3C1)=O)(CC)O)=N2)NC(COCNC(CNC([C@H](CC1C=CC=CC=1)NC(CNC(CNC(CCCCCN1C(C=CC1=O)=O)=O)=O)=O)=O)=O)=O
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| InChi Key |
WXNSCLIZKHLNSG-MCZRLCSDSA-N
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| InChi Code |
InChI=1S/C52H56FN9O13/c1-3-52(73)33-19-38-48-31(24-62(38)50(71)32(33)25-75-51(52)72)47-35(14-13-30-28(2)34(53)20-36(60-48)46(30)47)58-43(67)26-74-27-57-41(65)22-56-49(70)37(18-29-10-6-4-7-11-29)59-42(66)23-55-40(64)21-54-39(63)12-8-5-9-17-61-44(68)15-16-45(61)69/h4,6-7,10-11,15-16,19-20,35,37,73H,3,5,8-9,12-14,17-18,21-27H2,1-2H3,(H,54,63)(H,55,64)(H,56,70)(H,57,65)(H,58,67)(H,59,66)/t35-,37-,52-/m0/s1
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| Chemical Name |
Glycinamide, N-[6-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-1-oxohexyl]glycylglycyl-L-phenylalanyl-N-[[2-[[(1S,9S)-9-ethyl-5-fluoro-2,3,9,10,13,15-hexahydro-9-hydroxy-4-methyl-10,13-dioxo-1H,12Hbenzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl]amino]-2-oxoethoxy]methyl]-
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| Synonyms |
Deruxtecan; DS-8201a; DS8201a; DX-8951 derivative; Trastuzumab deruxtecan; DS 8201a; exatecan derivative; DX 8951; DX8951; Deruxtecan; 1599440-13-7; Mc-ggfg-dxd(1); 5SEB972CO4; N-((S)-10-Benzyl-1-(((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-1,6,9,12,15-pentaoxo-3-oxa-5,8,11,14-tetraazahexadecan-16-yl)-6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamide; 6-(2,5-dioxopyrrol-1-yl)-N-[2-[[2-[[(2S)-1-[[2-[[2-[[(10S,23S)-10-ethyl-18-fluoro-10-hydroxy-19-methyl-5,9-dioxo-8-oxa-4,15-diazahexacyclo[14.7.1.02,14.04,13.06,11.020,24]tetracosa-1,6(11),12,14,16,18,20(24)-heptaen-23-yl]amino]-2-oxoethoxy]methylamino]-2-oxoethyl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-2-oxoethyl]amino]-2-oxoethyl]hexanamide; Deruxtecan [USAN]; UNII-5SEB972CO4;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years Note: (1) This product is not stable in solution, please use freshly prepared working solution for optimal results. (2) This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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 : ~35 mg/mL (~33.85 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 1.75 mg/mL (1.69 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 17.5 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: 1.75 mg/mL (1.69 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 17.5 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: ≥ 1.75 mg/mL (1.69 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: 1.75 mg/mL (1.69 mM) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.9671 mL | 4.8354 mL | 9.6707 mL | |
| 5 mM | 0.1934 mL | 0.9671 mL | 1.9341 mL | |
| 10 mM | 0.0967 mL | 0.4835 mL | 0.9671 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04644237 | Active, not recruiting | Drug: Trastuzumab deruxtecan |
Non-Small Cell Lung Cancer | Daiichi Sankyo,Inc. | March 19, 2021 | Phase 2 |
| NCT04619004 | Active, not recruiting | Drug: Patritumab Deruxtecan (Fixed dose) |
Non-Small Cell Lung Cancer Metastatic |
Daiichi Sankyo,Inc. | February 2, 2021 | Phase 2 |
| NCT05458401 | Recruiting | Drug: Trastuzumab deruxtecan |
HER2-positive Breast Cancer | Daiichi Sankyo,Inc. | November 11, 2022 |
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