A 4-aminoquinoline derivative that markedly sensitizes tumor cell killing by Akt inhibitors with a minimum cytotoxicity to non-cancer cells

作者：Hu Changkun; Solomon V Raja; Cano Pablo; Lee Hoyun^*

来源：European Journal of Medicinal Chemistry, 2010, 45(2): 705-709.

DOI：10.1016/j.ejmech.2009.11.017

• Chloroquine analog
• Akt inhibitor
• Breast cancer
• Chemotherapeutics
• 184B5

The purpose of this study was to evaluate the enhancement value of chloroquine analogs when used in combination with Akt inhibitors on the MDA-MB468, MDA-MB231 and MCF7 human breast cancer cell lines. The result showed that the combination of certain chloroquine analogs and Akt inhibitors are highly effective. In particular, the chloroquine analog N'-(7-fluoro-quinolin-4-yl)-N,N-dimethyl-ethane-1,2-diamine (compound 5) was highly effective in sensitizing cancer cell killing when combined with either Akt inhibitor 8 (1-{1-[4-(7-phenyl-1H-imidazo[4,5-g]quinoxalin-6-yl)-benzyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one) or 9 ([4-(2-chloro-4a,10a-dihydro-phenoxazin-10-yl)-butyl]-diethylamine hydrochloride). Importantly, the enhancement of chloroquine analogs 5 on cell killing by Akt inhibitors 8 and 9 was cancer-specific. Thus, this combinational approach is highly promising in controlling tumors with a minimum side effect. Structural analysis of effective and ineffective chloroquine analogs suggests that the 4-aminoquinoline scaffold and lateral side chain of dimethylamino functionality play an important role for the enhancement of cell killing by Akt inhibitors.

• 出版日期2010-2