YU238259 (YU-238259) Is a novel and potent HDR (Homology-Dependent DNA Repair) inhibitor with anticancer activity. YU238259 may have clinical benefit to patients with advanced BRCA2-negative tumors, either as a monotherapy or as an adjuvant to radiotherapy and certain chemotherapies. In the presence of DNA repair and damage response defects, YU238259 displays strong synthetic lethality. In cellular GFP reporter assays, YU238259 specifically inhibits homology-dependent DNA repair but not non-homologous end-joining. Along with ionizing radiation, etoposide, and PARP inhibition, treatment with YU238259 also works well together. What's more, BRCA2 deficiency amplifies this interaction.
Physicochemical Properties
| 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 |
| 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) |
Biological Activity
| Targets | HDR |
| 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]. |
| ln Vivo | YU238259 (3 mg/kg, i.p.) inhibits the growth of BRCA2-deficient tumor xenografts in nude mice[1]. |
| 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). |
| 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]. |
| References |
[1]. YU238259 Is a Novel Inhibitor of Homology-Dependent DNA Repair That Exhibits Synthetic Lethality and Radiosensitization in Repair-Deficient Tumors. Mol Cancer Res. 2015 Oct;13(10):1389-97. |
Solubility Data
| 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 |