Identification of a Wells-Dawson polyoxometalatebased AP-2γ inhibitor with pro-apoptotic activity

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

doi:10.1042/BCJ20170942

Identification of a Wells-Dawson polyoxometalatebased AP-2γ inhibitor with pro-apoptotic activity

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

10 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	1965-1977
Number of pages	13
Journal	Biochemical Journal
Volume	475
Issue number	11
DOIs	https://doi.org/10.1042/BCJ20170942
Publication status	Published - 11 Jun 2018
Externally published	Yes

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Hu, J., Tan, S. K., Lim, M. G. L., Chang, S. H., Cui, G., Liu, S., Narasimhan, K., New, S. Y., Wang, X., Chen, C., Chakravarty, H., Kolatkar, P. R., Tam, K. Y., Lu, Q., Su, X., Jauch, R., & Cheung, E. (2018). Identification of a Wells-Dawson polyoxometalatebased AP-2γ inhibitor with pro-apoptotic activity. Biochemical Journal, 475(11), 1965-1977. https://doi.org/10.1042/BCJ20170942

@article{a1740a3e615b41d1a9437d084b25debe,

title = "Identification of a Wells-Dawson polyoxometalatebased AP-2γ inhibitor with pro-apoptotic activity",

abstract = "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.",

author = "Jiamiao Hu and Tan, {Si Kee} and Lim, {Michelle Gek Liang} and Chang, {Shie Hong} and Guimei Cui and Shanshan Liu and Kamesh Narasimhan and New, {Siu Yee} and Xuecong Wang and Congling Chen and Harapriya Chakravarty and Kolatkar, {Prasanna R.} and Tam, {Kin Yip} and Qian Lu and Xiaodi Su and Ralf Jauch and Edwin Cheung",

note = "Publisher Copyright: {\textcopyright} 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.",

year = "2018",

month = jun,

day = "11",

doi = "10.1042/BCJ20170942",

language = "English",

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TY - JOUR

T1 - Identification of a Wells-Dawson polyoxometalatebased AP-2γ inhibitor with pro-apoptotic activity

AU - Hu, Jiamiao

AU - Tan, Si Kee

AU - Lim, Michelle Gek Liang

AU - Chang, Shie Hong

AU - Cui, Guimei

AU - Liu, Shanshan

AU - Narasimhan, Kamesh

AU - New, Siu Yee

AU - Wang, Xuecong

AU - Chen, Congling

AU - Chakravarty, Harapriya

AU - Kolatkar, Prasanna R.

AU - Tam, Kin Yip

AU - Lu, Qian

AU - Su, Xiaodi

AU - Jauch, Ralf

AU - Cheung, Edwin

PY - 2018/6/11

Y1 - 2018/6/11

N2 - 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.

AB - 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.

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DO - 10.1042/BCJ20170942

M3 - Article

C2 - 29760237

AN - SCOPUS:85048652617

SN - 0264-6021

VL - 475

SP - 1965

EP - 1977

JO - Biochemical Journal

JF - Biochemical Journal

IS - 11

ER -

Identification of a Wells-Dawson polyoxometalatebased AP-2γ inhibitor with pro-apoptotic activity

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