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Purity: =100%
| ln Vitro |
The structures of CP5V (apcin-A-PEG5-VHL1) and VHL-CP5V-Cdc20 complex were generated using as templates the Protein Data Bank (PDB) structures with ids 5T35 and 4N14 for the VHL1 and apcin-A fragments, respectively. [1]
the Cdc20 small molecule inhibitors apcin (APC inhibitor) and apcin-A, which can competitively occupy the D-box binding pocket of Cdc20 to inhibit the ubiquitination of Cdc20 substrates, as well as small molecule inhibitors that antagonize the APC/C-Cdc20 interaction, TAME and proTAME. [1] |
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| Enzyme Assay |
Apcin-A is utilized as Cdc20 targeting ligand, and VHL and CRBN binding moieties VHL1 and thalidomide are respectively used to recruit the VHL/VBC complex and Celebron E3 ligase in the Cdc20 PROTACs. A series of polyethylene glycol (PEG) molecules were used to link apcin-A and VHL1/thalidomide.[1]
CP5V was designed based on apcin-A with a medium binding affinity. Lead optimization methods could be used to develop more potent Cdc20 inhibitors . Apcin and apcin-A have similar binding affinities14 and they do not interact directly with the polar residues around the D-box binding sites . The low binding affinity of apcin-P indicates that the aromatic group of the pyrimidine ring in apcin (and apcin-A), which interacts with Trp209, is important to enable stronger affinity14. [1] We decided to develop a novel chimera molecule, utilizing the PROTAC platform, to circumvent the challenges met by current Cdc20 small molecule inhibitors. Based on the feature that apcin-A can efficiently bind to Cdc20 and is easier to modify, we used apcin-A rather than apcin as the warhead to target Cdc20 . Regarding the E3 ligase recruited for Cdc20 ubiquitination followed by proteolysis, we considered VHL/VBC (VHL-Elongin BC) and CRBN (Celebron), both of which have reliable binding moieties (VHL ligand 1 or VHL1, and thalidomide, respectively) that have been applied in the design of several PROTAC molecules16,17,23. To search for an optimal chemical linker maximizing the formation of a stable Cdc20-PROTAC-VHL/VBC ternary complex, we have designed and tested a series of PEG-based linkers with different lengths, such as PEG2, PEG3, PEG4, PEG5, PEG6, PEG7, and PEG9. |
| References |
| Molecular Formula |
C10H14CL3N5O2
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|---|---|
| Molecular Weight |
342.609458446503
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| Exact Mass |
341.02
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| Elemental Analysis |
C, 35.06; H, 4.12; Cl, 31.04; N, 20.44; O, 9.34
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| CAS # |
1683617-62-0
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| Related CAS # |
1683535-53-6 (HCL)
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| PubChem CID |
127243466
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| Appearance |
Off-white to yellow solid powder
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| LogP |
2.2
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
20
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| Complexity |
297
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
JQTSJVDIFMKETH-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C10H14Cl3N5O2/c11-10(12,13)7(17-8-15-4-2-5-16-8)18-9(19)20-6-1-3-14/h2,4-5,7H,1,3,6,14H2,(H,18,19)(H,15,16,17)
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| Chemical Name |
3-aminopropyl N-[2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl]carbamate
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| Synonyms |
Apcin-A
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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: ~100 mg/mL (~291.9 mM
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (7.30 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 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 (7.30 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 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 (7.30 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.9188 mL | 14.5939 mL | 29.1877 mL | |
| 5 mM | 0.5838 mL | 2.9188 mL | 5.8375 mL | |
| 10 mM | 0.2919 mL | 1.4594 mL | 2.9188 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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