| Targets |
Cereblon
|
|---|---|
| ln Vivo |
Poly(ADP-ribose) polymerase (PARP) has emerged as an important molecular target for the treatment of several oncological diseases. A couple of molecular probes based on Olaparib scaffold have been developed by incorporation of F-18 or fluorophore for positron emission tomography (PET) or optical imaging in several types of tumor. PARP has been reported overexpressed in mesothelioma. We hereby synthesized an analogue of Olaparib containing DOTA moiety and radiolabeled it with Cu-64 to evaluate its utility of PET tracer for mesothelioma. The Cu-64 labeling was conveniently achieved at 90% yield with final compound at >99% radiochemistry purity. The biodistribution and PET imaging were performed at 0.5, 1, 2 and 18h to confirm the in vivo tumor targeting. The tumor uptake in study group was significant higher than that in control group (3.45±0.47% ID/g vs 2.26±0.30% ID/g) and tumor were clearly detected by PET imaging. These results suggest the feasibility to develop an Olaparib-based theranostic agent for mesothelioma [1].
|
| References | |
| Additional Infomation |
Inspired by the successful application of dual-target drugs (especially bispecific antibodies), we proposed to combine the concept of protein hydrolysis-targeted chimeras (PROTACs) with the dual-target strategy to design and synthesize dual-target PROTAC molecules that can simultaneously degrade two completely different types of targets. We rationally designed and prepared a series of novel dual-target PROTAC molecules. Efficient synthesis was achieved by using a convergent synthesis strategy. These dual-target PROTAC structures use trifunctional natural amino acids as star-shaped core linkers to link two independent inhibitors and E3 ligands together. In this study, novel dual-target PROTACs were synthesized using gefitinib, olaparib, and CRBN or VHL E3 ligands as substrates. The results showed that these PROTACs can simultaneously degrade epidermal growth factor receptor (EGFR) and poly(ADP-ribose) polymerase (PARP) in cancer cells. As the first successful example of dual PROTACs, this technology will greatly broaden the application scope of the PROTAC method and open up new areas for drug discovery. [2]
|
| Molecular Formula |
C20H19FN4O2
|
|---|---|
| Molecular Weight |
366.389
|
| Exact Mass |
366.149
|
| CAS # |
763111-47-3
|
| PubChem CID |
11726399
|
| Appearance |
White to off-white solid powder
|
| LogP |
2.377
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
5
|
| Rotatable Bond Count |
3
|
| Heavy Atom Count |
27
|
| Complexity |
605
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
C1CN(CCN1)C(=O)C2=C(C=CC(=C2)CC3=NNC(=O)C4=CC=CC=C43)F
|
| InChi Key |
MFFUYEOGICAKCK-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C20H19FN4O2/c21-17-6-5-13(11-16(17)20(27)25-9-7-22-8-10-25)12-18-14-3-1-2-4-15(14)19(26)24-23-18/h1-6,11,22H,7-10,12H2,(H,24,26)
|
| Chemical Name |
4-[[4-fluoro-3-(piperazine-1-carbonyl)phenyl]methyl]-2H-phthalazin-1-one
|
| Synonyms |
N-Descyclopropanecarbaldehyde Olaparib; 763111-47-3; 4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one; 4-[[4-fluoro-3-(piperazine-1-carbonyl)phenyl]methyl]-2H-phthalazin-1-one; N-Descyclopropanecarbaldehyde Olaparib; MFCD18251631; 1-[5-[(3,4-Dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoyl]piperazine; 4-[[4-Fluoro-3-(1-piperazinylcarbonyl)phenyl]methyl]-1(2H)-phthalazinone; 4-{[4-fluoro-3-(piperazine-1-carbonyl)phenyl]methyl}-1,2-dihydrophthalazin-1-one;
|
| 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 |
| 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) |
DMSO : ≥ 100 mg/mL (~272.9 mM)
H2O : < 0.1 mg/mL |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.82 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 (6.82 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 (6.82 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 | 2.7293 mL | 13.6467 mL | 27.2933 mL | |
| 5 mM | 0.5459 mL | 2.7293 mL | 5.4587 mL | |
| 10 mM | 0.2729 mL | 1.3647 mL | 2.7293 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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