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D-I03 (DI03) is a novel and potent RAD52 inhibitor (Kd = 25.8 µM) with anticancer activity. RAD52 is a member of the homologous recombination (HR) pathway that is important for maintenance of genome integrity. While RAD52 mutations alone do not significantly affect a mammal's phenotype, they can be fatal when combined with mutations in other genes, such as BRCA1, BRCA2, PALB2, and RAD51C, that result in ovarian and breast cancer that is inherited. As such, RAD52 might be a crucial target for cancer treatment. D-I03 inhibits the growth of BRCA1- and BRCA2-deficient cells and prevents SSA and D-loop formation that are dependent on RAD52. also prevents the development of RAD52 foci brought on by damage, but has no effect on RAD51 foci brought on by cisplatin.
| Targets |
RAD52 ( Ki = 25.8 µM )
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|---|---|
| ln Vitro |
D-I03 (0-10 μM; on days 1 and 3; Capan-1 and UWB1.289 cells) treatment preferentially inhibited the growth of UWB1.289 and Capan-1 cells in a concentration-dependent manner[1].
D-I03 inhibits the formation of RAD52 foci in BCR-ABL1-positive, BRCA1-deficient 32Dcl3 murine hematopoietic cell line, which expresses GFP-RAD52, in response to cisplatin. The percentage of cells with RAD52 foci drops from 38.7% to 171% in the presence of D-I03 (2.5 μM); concurrently, the percentage of cells treated with ciprofloxacin without foci rises from 48.4% to 71.9%. ? D-I03 has no effect on RAD51 foci that are brought on by cisplatin. D-I03 exhibits low genotoxicity as evidenced by its inability to induce either RAD51 or RAD52 foci in BRCA1-deficient cells when used alone [1]. |
| ln Vivo |
D-I03 (50 mg/kg/day; intraperitoneal injection; daily; for 7 days; nu/nu mice) treatment slows the growth of MDA-MB-436 tumors that lack BRCA1. Talazoparib puls D-I03 exhibits negligible toxicity against normal tissues and organs and has no effect on the growth of tumors that are BRCA1-proficient[3]. The results of pharmacokinetic and toxicity studies show that D-I03 has a maximal concentration in peripheral blood of >1 μM at a maximal tolerated dose of ≥50 mg/kg and t1/2 of 23.4 hours[1].
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| Cell Assay |
Cell Line: Capan-1 (BRCA2−) and UWB1.289 (BRCA1+) cells
Concentration: 0 μM, 2.5 μM, 5 μM, or 10 μM Incubation Time: On days 1 and 3 Result: Preferentially suppressed the growth of Capan-1 and UWB1.289 cells. |
| Animal Protocol |
Nu/nu mice injected with BRCA1-deficient MDA-MB-436 cells
50 mg/kg/day Intraperitoneal injection; daily; for 7 days |
| References |
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| Molecular Formula |
C23H36N6S
|
|---|---|
| Molecular Weight |
428.6371
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| Exact Mass |
428.27
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| Elemental Analysis |
C, 64.45; H, 8.47; N, 19.61; S, 7.48
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| CAS # |
688342-78-1
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| PubChem CID |
24761372
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| Appearance |
Off-white to light yellow solid powder
|
| LogP |
3.6
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
30
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| Complexity |
520
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
UXDGHRWOHOPKIL-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H36N6S/c1-5-27(6-2)11-10-24-23(30)25-19-8-9-21-20(17-19)18(4)16-22(26-21)29-14-12-28(7-3)13-15-29/h8-9,16-17H,5-7,10-15H2,1-4H3,(H2,24,25,30)
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| Chemical Name |
1-[2-(diethylamino)ethyl]-3-[2-(4-ethylpiperazin-1-yl)-4-methylquinolin-6-yl]thiourea
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| Synonyms |
DI03; D I03; D-I03
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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: 50~86 mg/mL (116.7~200.6 mM)
Ethanol: ~10 mg/mL |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.83 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 (5.83 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 (5.83 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 | 2.3330 mL | 11.6648 mL | 23.3296 mL | |
| 5 mM | 0.4666 mL | 2.3330 mL | 4.6659 mL | |
| 10 mM | 0.2333 mL | 1.1665 mL | 2.3330 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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