| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
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| Other Sizes |
| Targets |
Topoisomerase; Camptothecins
|
|---|---|
| References | |
| Additional Infomation |
Topoisomerase I (TOP1) inhibitors represent an emerging class of payloads for constructing antibody-drug conjugates (ADCs) as next-generation cancer therapeutics. Existing ADCs utilize camptothecin, a less potent payload, and exhibit limited cycling stability. This study proposes a novel camptothecin-based linker-payload platform based on the highly efficient camptothecin derivative ethatecan. First, we elucidate the challenges posed by the hydrophobic combination of ethatecan with the known dipeptide-p-aminobenzylcarbamate (PAB) cleavage site, such as reduced antibody conjugation yield and ADC aggregation. After evaluating various linker-payload structures, we found that combining ethynylphosphonamide with a separate PEG24 chain effectively compensates for the hydrophobicity of the PAB-ethatecan moiety. Furthermore, we demonstrate that the identified linker-payload structure enables the construction of high-drug-load DAR8 ADCs with excellent solubility. Compared directly with the approved camptothecin antibody-drug conjugate (ADC) Enhertu, the results showed that the ADC based on the novel essanotecan linker-payload platform had stronger targeted killing ability of tumor cells, excellent bystander killing ability, significantly improved in vitro and in vivo linker stability, and better in vivo efficacy at four tested dose levels in xenograft models. In addition, we found that even when each antibody was loaded with eight drug molecules, the ADC based on the novel essanotecan linker-payload platform still exhibited similar pharmacokinetic characteristics to the antibody. This ADC platform provides a new universal solution that can deliver TOP1 inhibitors to the tumor site with the highest efficiency, without being limited by the antibody and its target, and therefore can be widely used in a variety of cancer indications. [1]
|
| Molecular Formula |
C100H151FN9O36P
|
|---|---|
| Molecular Weight |
2105.3
|
| Exact Mass |
2103.99833
|
| CAS # |
2928571-43-9
|
| PubChem CID |
172653110
|
| Appearance |
White to off-white solid powder
|
| Density |
1.31±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)
|
| LogP |
-1.1
|
| Hydrogen Bond Donor Count |
9
|
| Hydrogen Bond Acceptor Count |
39
|
| Rotatable Bond Count |
90
|
| Heavy Atom Count |
147
|
| Complexity |
3780
|
| Defined Atom Stereocenter Count |
4
|
| SMILES |
CC[C@@]1(C2=C(COC1=O)C(=O)N3CC4=C5[C@H](CCC6=C5C(=CC(=C6C)F)N=C4C3=C2)NC(=O)OCC7=CC=C(C=C7)NC(=O)[C@H](CCCNC(=O)N)NC(=O)[C@H](C(C)C)NC(=O)C8=CC=C(C=C8)NP(=O)(C#C)OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO)O
|
| InChi Key |
KZEPGSKCAWPFGG-HTZDUXJFSA-N
|
| InChi Code |
InChI=1S/C100H151FN9O36P/c1-6-100(119)83-69-88-92-81(71-110(88)96(115)82(83)73-144-97(100)116)90-85(19-18-80-75(5)84(101)70-87(105-92)89(80)90)107-99(118)145-72-76-10-14-78(15-11-76)104-94(113)86(9-8-20-103-98(102)117)106-95(114)91(74(3)4)108-93(112)77-12-16-79(17-13-77)109-147(120,7-2)146-68-67-143-66-65-142-64-63-141-62-61-140-60-59-139-58-57-138-56-55-137-54-53-136-52-51-135-50-49-134-48-47-133-46-45-132-44-43-131-42-41-130-40-39-129-38-37-128-36-35-127-34-33-126-32-31-125-30-29-124-28-27-123-26-25-122-24-23-121-22-21-111/h2,10-17,69-70,74,85-86,91,111,119H,6,8-9,18-68,71-73H2,1,3-5H3,(H,104,113)(H,106,114)(H,107,118)(H,108,112)(H,109,120)
|
| Chemical Name |
[4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-2-[[4-[[ethynyl-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]phosphoryl]amino]benzoyl]amino]-3-methylbutanoyl]amino]pentanoyl]amino]phenyl]methyl 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]carbamate
|
| Synonyms |
H9Q9Q9Z3PF; P5(PEG24)-VC-PAB-exatecan; 2928571-43-9
|
| 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 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)
|
| Solubility (In Vitro) |
Typically soluble in DMSO (e.g. 10 mM)
|
|---|---|
| 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 | 0.4750 mL | 2.3750 mL | 4.7499 mL | |
| 5 mM | 0.0950 mL | 0.4750 mL | 0.9500 mL | |
| 10 mM | 0.0475 mL | 0.2375 mL | 0.4750 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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