| Description: |
KU-0060648 is a dual inhibitor of PI3K and DNA-PK with IC50s of 4 nM, 0.5 nM, 0.1 nM, 0.594 nM and 8.6 nM for PI3Kα, PI3Kβ, PI3Kγ, PI3Kδ and DNA-PK, respectively[1]. |
| Target: |
PI3Kα:4 nM (IC50)
PI3Kβ:0.5 nM (IC50)
PI3Kγ:0.594 μM (IC50)
PI3Kδ:0.1 nM (IC50)
DNA-PK:8.6 nM (IC50) |
| In Vivo: |
KU-0060648 (intraperitoneal injection; 10 and 50 mg/kg; once daily; daily for 21 days) dramatically inhibits HepG2 xenograft growth in nude mice, the tumor weights (at week 5) of KU-0060648 group mice are dramatically lighter than that of vehicle control mice and exert a dose-dependent effect in vivo[1]. Animal Model: HepG2 xenograft nude mice model[1] Dosage: 10 and 50 mg/kg Administration: Intraperitoneal injection; 10 and 50 mg/kg; once daily; daily for 21 days Result: Suppressed HepG2 xenograft growth in nude mice. |
| In Vitro: |
KU-0060648 inhibits cellular DNA-PK auto-phosphorylation with IC50 values of 0.019 μM (MCF7 cells) and 0.17 μM (SW620 cells), and PI-3K-mediated AKT phosphorylation with IC50 values of 0.039 μM (MCF7 cells) and >10 μM (SW620 cells)[1]. KU-0060648 (30-500 nM; 72 hours) dose-dependently inhibits HepG2 cell proliferation, IC50=134.32nM[2]. KU-0060648 (0.1-1 μM；5 days) inhibits cell lines growth with GI50s of 0.95 μM, 0.21 μM, 0.27 μM, 0.41 μM and 1 μM in SW620, LoVo, MCF7, T47D and MDA-MB-231 cells[1]. KU-0060648 (100-300 nM;12 hours) significantly inhibits activation of PI3K (p85 phosphorylation), AKT (Ser-473 and Thr-308 phosphorylations) and mTOR (p70S6K1 Thr-389 phosphorylation) in HepG2/Huh-7 lines and primary human HCC cells[2]. Cell Proliferation Assay[1] Cell Line: Human breast (MCF7, T47D and MDA-MB-231) and colon (LoVo and SW620) cancer cells Concentration: 0.1-1 μM Incubation Time: 5 days Result: Resulted in> 50% inhibition of cell growth in all cell lines. Western Blot Analysis[2] Cell Line: HCC cells; HepG2/Huh-7 cells Concentration: 100-300 nM Incubation Time: 12 hours Result: Inhibited phosphatidylinositol 3-kinase (PI3K) and in-activates AKT-mTOR signaling. |
| References: |
[1]. Munck JM, et al. Chemosensitization of cancer cells by KU-0060648, a dual inhibitor of DNA-PK and PI-3K. Mol Cancer Ther. 2012 Aug;11(8):1789-98.
[2]. Chen MB, et al. KU-0060648 inhibits hepatocellular carcinoma cells through DNA-PKcs-dependent and DNA-PKcs-independent mechanisms. Oncotarget. 2016 Mar 29;7(13):17047-59. |
