| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| 100mg |
|
||
| 250mg | |||
| 500mg | |||
| Other Sizes |
Purity: ≥98%
| Targets |
HDR
YU238259 targets homology-dependent DNA repair (HDR), a critical pathway for maintaining genome stability by accurately repairing DNA double-strand breaks using a homologous template. The compound specifically inhibits HDR while having no effect on PARP activity. By inhibiting HDR, YU238259 causes synthetic lethality in cells with defects in other DNA repair pathways, such as BRCA2-deficient cells. The compound shows synergism with radiotherapy and DNA-damaging chemotherapy that is potentiated by BRCA2 loss. |
|---|---|
| ln Vitro |
YU238259 is an inhibitor of homology-dependent DNA repair, with no effect on PARP activity. YU238259 exhibits cytotoxicity in BRCA2-deficient cells and has a low LD50 of 8.5 μM. In U2OS DR-GFP or U2OS EJ5-GFP cells, YU238259 (0–5 μM) significantly lowers HDR efficiency in a dose-dependent manner while having no impact on NHEJ frequency. YU238259 (0–10 M) exhibits synthetic lethality with loss of frequently mutated tumor suppressors and exhibits synergism with radiation therapy (IR) and chemotherapy that damages DNA and is amplified by BRCA2 loss[1].
In vitro, YU238259 is an inhibitor of homology-dependent DNA repair with no effect on PARP activity. It shows cytotoxicity in BRCA2-deficient cells with a low LD50 of 8.5 μM. YU238259 at 0-5 μM causes a potent, dose-dependent decrease in HDR efficiency in U2OS DR-GFP or U2OS EJ5-GFP cells, but with no effect on NHEJ frequency. YU238259 at 0-10 μM exhibits synthetic lethality with loss of frequently mutated tumor suppressors. The compound shows synergism with radiotherapy and DNA-damaging chemotherapy. |
| ln Vivo |
YU238259 (3 mg/kg, i.p.) inhibits the growth of BRCA2-deficient tumor xenografts in nude mice[1].
In vivo, YU238259 has demonstrated anti-tumor efficacy in xenograft mouse models. YU238259 at 3 mg/kg administered intraperitoneally inhibits the growth of BRCA2-deficient tumor xenografts in nude mice. The compound significantly delays tumor growth of BRCA2-deficient human tumor xenografts. These in vivo studies confirm the compound's synthetic lethality approach and its potential for treating cancers with DNA repair defects. Further studies would be required to fully characterize its efficacy and safety. |
| Enzyme Assay |
In vitro enzyme/receptor binding assays for YU238259 are not typically performed because the compound targets a cellular DNA repair pathway rather than an enzyme or receptor. However, the compound's ability to inhibit HDR can be assessed using cell-free DNA repair assays. In these assays, the repair of DNA substrates by cell extracts is measured in the presence of varying concentrations of YU238259. The compound's specificity for HDR over NHEJ can be confirmed using appropriate DNA substrates. These assays confirm the compound's mechanism of action as an HDR inhibitor.
|
| Cell Assay |
U2OS cells were pretreated with 25 μM YU238259 or DMSO vehicle for 1 h and cells were then irradiated with 10 Gy IR. After 8 hours of IR, cells were fixed, stained with antibodies and Hoechst dye, and imaged. The YCMD InCell Analyzer algorithm was used to measure foci. Cells were deemed foci-positive if they had ≥15 foci (BRCA1, pDNA-PK), or ≥20 foci (53BP1).
In vitro cellular assays for YU238259 are performed using cell lines with defined DNA repair capabilities, such as U2OS DR-GFP cells (for HDR measurement) and U2OS EJ5-GFP cells (for NHEJ measurement). Cells are treated with varying concentrations of YU238259, and HDR or NHEJ efficiency is measured by flow cytometry or fluorescence microscopy based on GFP reporter expression. Cytotoxicity is assessed using MTT or CellTiter-Glo assays in BRCA2-proficient and BRCA2-deficient cells. These assays confirm the compound's selective inhibition of HDR and its synthetic lethality in DNA repair-deficient cells. |
| Animal Protocol |
At the age of 4-5 weeks, 3 106 DLD-1 or DLD-1 BRCA2-KO cells suspended in 100 μL PBS are subcutaneously injected into 069(nu)/070(nu/+) athymic nude mice. Over 80% of tumors survive. The mice are injected with 3 mg/kg of YU238259 or its 3:1 DMSO:PBS vehicle, or 5 mg/kg of YU128440 or its 1:19 DMSO:PBS vehicle, when the tumors reach 100 mm3 geometric mean volume (IP, 100 μL total in each case). There are three treatments per 3×/week (Mon/Wed/Fri), totaling 12 doses of YU238259 and 4 doses of YU128440. Using an external caliper, tumor growth is evaluated. When a mouse's tumor volume exceeds 1000 mm3, the animal is put to death[1].
In vivo animal experiments for YU238259 are conducted in xenograft mouse models of BRCA2-deficient tumors. Immunocompromised nude mice are implanted with BRCA2-deficient human tumor cells and treated with YU238259 via intraperitoneal administration at doses such as 3 mg/kg. Tumor growth inhibition is monitored, and endpoints include tumor volume, tumor weight, and survival. The compound's effects on DNA damage markers in tumor tissues are assessed by immunohistochemistry or Western blotting. |
| ADME/Pharmacokinetics |
YU238259 has a molecular weight of 459.95 g/mol and a molecular formula of C22H22ClN3O4S. The compound is soluble in DMSO at concentrations up to 84 mg/mL (182.6 mM), but is slightly soluble or insoluble in ethanol and water. It is stable as a powder at -20°C for up to 3 years. For in vivo administration, it can be formulated in appropriate vehicles for intraperitoneal injection. Detailed pharmacokinetic properties have not been extensively reported.
|
| Toxicity/Toxicokinetics |
The toxicological profile of YU238259 has not been extensively characterized in publicly available literature. As a DNA repair inhibitor, YU238259 has potential toxicity to normal cells, particularly those with active DNA repair pathways. However, its synthetic lethality approach suggests selectivity for cancer cells with DNA repair defects. Standard toxicology studies, including assessment of cytotoxicity in normal cell lines and acute toxicity in animal models, would be necessary to establish its safety profile.
|
| References | |
| Additional Infomation |
YU238259 is a novel inhibitor of homology-dependent DNA repair (HDR) that exhibits potent synthetic lethality in the setting of DNA damage response and DNA repair defects. It specifically inhibits HDR while not inhibiting non-homologous end-joining (NHEJ). YU238259 shows cytotoxicity in BRCA2-deficient cells with a low LD50 of 8.5 μM and synergizes with radiotherapy and DNA-damaging chemotherapy. The compound significantly delays tumor growth of BRCA2-deficient human tumor xenografts in nude mice. YU238259 is a research compound for cancer research and is not an approved drug.
|
| Molecular Formula |
C22H22CLN3O4S
|
|---|---|
| Molecular Weight |
459.945783138275
|
| Exact Mass |
459.102
|
| Elemental Analysis |
C, 57.45; H, 4.82; Cl, 7.71; N, 9.14; O, 13.91; S, 6.97
|
| CAS # |
1943733-16-1
|
| Related CAS # |
1943733-16-1
|
| PubChem CID |
121473004
|
| Appearance |
White to off-white solid powder
|
| LogP |
3.2
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
6
|
| Rotatable Bond Count |
9
|
| Heavy Atom Count |
31
|
| Complexity |
656
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
COC1=CC=C(C=C1)S(=O)(=O)NCC2=CC=C(C=C2)C(=O)NCCC3=NC=C(C=C3)Cl
|
| InChi Key |
BIHURSOREGLQBB-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C22H22ClN3O4S/c1-30-20-8-10-21(11-9-20)31(28,29)26-14-16-2-4-17(5-3-16)22(27)24-13-12-19-7-6-18(23)15-25-19/h2-11,15,26H,12-14H2,1H3,(H,24,27)
|
| Chemical Name |
N-[2-(5-chloropyridin-2-yl)ethyl]-4-[[(4-methoxyphenyl)sulfonylamino]methyl]benzamide
|
| Synonyms |
YU-238259; YU238259; YU 238259
|
| 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: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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: 91~110 mg/mL (197.9~239.2 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.75 mg/mL (5.98 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 27.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1741 mL | 10.8707 mL | 21.7415 mL | |
| 5 mM | 0.4348 mL | 2.1741 mL | 4.3483 mL | |
| 10 mM | 0.2174 mL | 1.0871 mL | 2.1741 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.
|
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
COA
