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Dxd, an exatecan analog, is a novel and potent DNA topoisomerase I inhibitor(IC50=0.31 μM) with anticancer activity, and is used as a conjugated drug of HER2-targeting ADC (DS-8201a).
| Targets |
Topoisomerase I ( IC50 = 0.31 μM ); Camptothecins
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|---|---|
| ln Vitro |
Dxd (Exatecan derivative for ADC) is a potent inhibitor of DNA topoisomerase I that is used as a conjugated drug with HER2-targeting ADC (DS-8201a), having an IC50 of 0.31 μM. With IC50s ranging from 1.43 nM to 4.07 nM, Dxd is cytotoxic to human cancer cell lines of KPL-4, NCI-N87, SK-BR-3, and MDA-MB-468; however, control IgG-ADC, of which Dxd is the payload, exhibits no inhibition on the four cell lines (expressing HER2). With IC50 values of 26.8, 25.4, and 6.7 ng/mL, respectively, DS-8201a (the payload is Dxd) exhibits significant suppression on the HER2-positive KPL-4, NCI-N87, and SK-BR-3 cell lines, but no such inhibition is seen on MDA-MB-468 (IC50, >10,000 ng/mL)[1].
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| ln Vivo |
DS-8201a (Dxd is the payload, 10 mg/kg, i.v.) demonstrates potent ntitumor activity in HER2-low-expressing ST565 and ST313 models with HER2 IHC 1+/FISH-negative expression as well as in HER2-positive models with KPL4, JIMT-1, and Capan-1[1].
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| Cell Assay |
A 96-well plate is seeded with 1,000 cells per well. Dxd is added following a night of incubation. A CellTiter-Glo Luminescent Cell Viability Assay is used to assess cell viability six days later. To identify HER2 expression in each cell line, FITC Mouse IgG1, κ Isotype Control, or anti-HER2/neu FITC are incubated on ice for 30 minutes. Following washing, FACSCalibur is used to analyze the labeled cells. The calculation of relative mean fluorescence intensity (rMFI) is done[1].
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| Animal Protocol |
Mice: In brief, specific pathogen-free female nude mice are subcutaneously injected with each cell suspension or tumor fragment. Dosing begins on day 0 and the tumor-bearing mice are randomized into treatment and control groups based on the tumor volumes once the tumor has grown to an appropriate size. The mice receive intravenous injections of DS-8201a (1 or 10 mg/kg, i.v.; Dxd is the payload). One calculates tumor growth inhibition (TGI, %)[1].
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| References |
| Molecular Formula |
C26H24FN3O6
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|---|---|
| Molecular Weight |
493.48367023468
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| Exact Mass |
493.16
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| Elemental Analysis |
C, 63.28; H, 4.90; F, 3.85; N, 8.52; O, 19.45
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| CAS # |
1599440-33-1
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| Related CAS # |
Exatecan;171335-80-1;Exatecan mesylate;169869-90-3;Dxd-d5;Exatecan mesylate dihydrate;197720-53-9
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| PubChem CID |
117888634
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
0
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
36
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| Complexity |
1080
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| Defined Atom Stereocenter Count |
2
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| SMILES |
CC[C@@]1(C2=C(COC1=O)C(=O)N3CC4=C5[C@H](CCC6=C5C(=CC(=C6C)F)N=C4C3=C2)NC(=O)CO)O
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| InChi Key |
PLXLYXLUCNZSAA-QLXKLKPCSA-N
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| InChi Code |
InChI=1S/C26H24FN3O6/c1-3-26(35)15-6-19-23-13(8-30(19)24(33)14(15)10-36-25(26)34)22-17(28-20(32)9-31)5-4-12-11(2)16(27)7-18(29-23)21(12)22/h6-7,17,31,35H,3-5,8-10H2,1-2H3,(H,28,32)/t17-,26-/m0/s1
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| Chemical Name |
N-[(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]-2-hydroxyacetamide
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| Synonyms |
DX-8951 derivative; DX-8951; DX8951; Exatecan derivative; Trastuzumab Deruxtecan (DS-8201a).
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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 |
| 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: 8~40 mg/mL (16.2~81.1 mM)
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0264 mL | 10.1321 mL | 20.2642 mL | |
| 5 mM | 0.4053 mL | 2.0264 mL | 4.0528 mL | |
| 10 mM | 0.2026 mL | 1.0132 mL | 2.0264 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 |
| NCT05280470 | Active Recruiting |
Drug: Ifinatamab Deruxtecan (I-DXd) |
Extensive-stage Small- cell Lung Cancer |
Daiichi Sankyo, Inc. | June 17, 2022 | Phase 2 |
| NCT05104866 | Active Recruiting |
Drug: Dato-DXd | Breast Cancer | AstraZeneca | October 18, 2021 | Phase 3 |
| NCT04556773 | Active Recruiting |
Drug: Durvalumab Drug: Paclitaxel |
Metastatic Breast Cancer | AstraZeneca | December 17, 2020 | Phase 1 |
| NCT04739761 | Active Recruiting |
Drug: Trastuzumab Deruxtecan | Breast Cancer | AstraZeneca | June 22, 2021 | Phase 3 |
| NCT04526691 | Active Recruiting |
Drug: Cisplatin Drug: Carboplatin |
Advanced or Metastatic NSCLC | Daiichi Sankyo, Inc. | September 15, 2020 | Phase 1 |
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