期刊
JOURNAL OF BIOMOLECULAR SCREENING
卷 18, 期 1, 页码 85-96出版社
SAGE PUBLICATIONS INC
DOI: 10.1177/1087057112453936
关键词
phosphatase; Eyes Absent 2; Eya2; Eya2 inhibitor; Six1
资金
- Molecular Libraries Initiative of the NIH Roadmap for Medical Research, National Institutes of Health, through NIH [R03DA030559]
- Department of Defense [BC084105]
- AACR/BCRF (American Association for Cancer Research and Breast Cancer Research Foundation)
- State of Colorado
- Colorado Bioscience Discovery and Evaluation Grant
- NATIONAL CANCER INSTITUTE [P30CA046934] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [ZIBTR000002, ZIBTR000004, UL1TR001082] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R03DA030559] Funding Source: NIH RePORTER
Eya proteins are essential coactivators of the Six family of homeobox transcription factors and also contain a unique protein tyrosine phosphatase activity, belonging to the haloacid dehalogenase family of phosphatases. The phosphatase activity of Eya is important for a subset of Six1-mediated transcription, making this a unique type of transcriptional control. It is also responsible for directing cells to the repair instead of apoptosis pathway upon DNA damage. Furthermore, the phosphatase activity of Eya is critical for transformation, migration, invasion, and metastasis of breast cancer cells. Thus, inhibitors of the Eya phosphatase activity may be antitumorigenic and antimetastatic, as well as sensitize cancer cells to DNA damage-inducing therapies. In this article, we identified a previously unknown chemical series using high-throughput screening that inhibits the Eya2 phosphatase activity with IC(50)s ranging from 1.8 to 79 mu M. Compound activity was confirmed using an alternative malachite green assay and H2AX, a known Eya substrate. Importantly, these Eya2 phosphatase inhibitors show specificity and do not significantly inhibit several other cellular phosphatases. Our studies identify the first selective Eya2 phosphatase inhibitors that can potentially be developed into chemical probes for functional studies of Eya phosphatase or into anticancer drugs in the future.
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