In vitro: YU238259 exhibits potent synthetic lethality in the setting of DNA damage response and DNA repair defects. Treatment with YU238259 is not only synergistic with ionizing radiation (IR), etoposide, and PARP inhibition, but this synergism is heightened by BRCA2-deficiency. Synthetic lethality of YU238259 in HDR-deficient cells results from accumulation of unresolved DSBs following additional inhibition of residual HDR pathway activity. Inhibition of HDR activity by YU238259 has little to no effect on the NHEJ pathway. YU238259 sensitizes tumor cells to radiation therapy and DSB-inducing chemotherapy.
In vivo: Growth of BRCA2-deficient human tumor xenografts in nude mice is significantly delayed by YU238259 treatment even in the absence of concomitant DNA-damaging therapy.
|Cell lines||U2OS cells|
|Preparation method||U2OS cells were pretreated with 25 μM YU238259 or DMSO vehicle for 1 h and cells were then irradiated with 10 Gy IR. Cells were fixed at 8 h post-IR, stained with antibodies and Hoechst dye, and imaged. Foci were quantified using the InCell Analyzer algorithm developed by YCMD. Cells were scored as foci-positive if they contained ≥15 foci (BRCA1, pDNA-PK) or ≥20 foci (53BP1).|
|Incubation time||1 h|
|Animal models||069(nu)/070(nu/+) athymic nude mice|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||91 mg/mL in DMSO|
YU238259 Is a Novel Inhibitor of Homology-Dependent DNA Repair That Exhibits Synthetic Lethality and Radiosensitization in Repair-Deficient Tumors.
Stachelek GC, et al. Mol Cancer Res. 2015 Oct;13(10):1389-97. PMID: 26116172.
|Related DNA-PK Products|
Compound 401 is a synthetic inhibitor of DNA-PK (IC50 = 0.28 μM) that also targets mTOR but not PI3K in vitro.
LTURM34 is a specific DNA-PK inhibitor, 170-fold more selective for DNA-PK activity compared to PI3K activity, with IC50 value of 0.034 μM.
KU-0060648 is a dual inhibitor of DNA-PK and PI3Kα, PI3Kβ, PI3Kδ with IC50 of 8.6 nM and 4 nM, 0.5 nM, 0.1 nM respectively, less inhibition of PI3Kγ with IC50 of 0.59 μM.
NU7026 is a DNA-PK inhibitor with IC50 of 0.23 μM.
Products are for research use only. Not for human use. We do not sell to patients.
© Copyright 2010-2017 AbMole BioScience. All Rights Reserved.