期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 62, 期 7, 页码 3407-3427出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b01888
关键词
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资金
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- Japan Agency for Medical Research and Development (AMED) [15cm0106004, JP15cm0106030, JP16cm0106102, JP17cm0106102, JP18cm0106102]
The canonical WNT pathway plays an important role in cancer pathogenesis. Inhibition of poly(ADP-ribose) polymerase catalytic activity of the tankyrases (TNKS/TNKS2) has been reported to reduce the Wnt/beta-catenin signal by preventing poly ADP-ribosylation-dependent degradation of AXIN, a negative regulator of Wnt/beta-catenin signaling. With the goal of investigating the effects of tankyrase and Wnt pathway inhibition on tumor growth, we set out to find small-molecule inhibitors of TNKS/TNKS2 with suitable drug-like properties. Starting from 1a, a high-throughput screening hit, the spiroindoline derivative 40c (RK-287107) was discovered as a potent TNKS/TNKS2 inhibitor with >7000-fold selectivity against the PARP1 enzyme, which inhibits WNT-responsive TCF reporter activity and proliferation of human colorectal cancer cell line COLO-320DM. RK-287107 also demonstrated dose-dependent tumor growth inhibition in a mouse xenograft model. These observations suggest that RK-287107 is a promising lead compound for the development of novel tankyrase inhibitors as anticancer agents.
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