AP-2 gamma (AP-2γ) is a transcription factor that plays pivotal roles in breast cancer biology. To search for small molecule inhibitors of AP-2γ, we performed a high-throughput fluorescence anisotropy screen and identified a polyoxometalate compound with Wells–Dawson structure K6[P2Mo18O62] (Dawson-POM) that blocks the DNA-binding activity of AP-2γ. We showed that this blocking activity is due to the direct binding of Dawson-POM to AP-2γ. We also provided evidence to show that Dawson-POM decreases AP-2γ-dependent transcription similar to silencing the gene. Finally, we demonstrated that Dawson-POM contains anti-proliferative and pro-apoptotic effects in breast cancer cells. In summary, we identified the first small molecule inhibitor of AP-2γ and showed Dawson-POM-mediated inhibition of AP-2γ as a potential avenue for cancer therapy.
Identification of a Wells–Dawson polyoxometalate-based AP-2γ inhibitor with pro-apoptotic activity
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Jiamiao Hu, Si Kee Tan, Michelle Gek Liang Lim, Shie Hong Chang, Guimei Cui, Shanshan Liu, Kamesh Narasimhan, Siu Yee New, Xuecong Wang, Congling Chen, Harapriya Chakravarty, Prasanna R. Kolatkar, Kin Yip Tam, Qian Lu, Xiaodi Su, Ralf Jauch, Edwin Cheung; Identification of a Wells–Dawson polyoxometalate-based AP-2γ inhibitor with pro-apoptotic activity. Biochem J 15 June 2018; 475 (11): 1965–1977. doi: https://doi.org/10.1042/BCJ20170942
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