Direct inhibition of hypoxia-inducible transcription factor complex with designed dimeric epidithiodiketopiperazine

Katherine M. Block; Hui Wang; Lajos Z. Szabó; Nathan W. Polaske; Laura K. Henchey; Ramin Dubey; Swati Kushal; Csaba F. László; Joshua Makhoul; Zuohe Song; Emmanuelle J. Meuillet; Bogdan Z. Olenyuk

doi:10.1021/ja807601b

Direct inhibition of hypoxia-inducible transcription factor complex with designed dimeric epidithiodiketopiperazine

Katherine M. Block, Hui Wang, Lajos Z. Szabó, Nathan W. Polaske, Laura K. Henchey, Ramin Dubey, Swati Kushal, Csaba F. László, Joshua Makhoul, Zuohe Song, Emmanuelle J. Meuillet, Bogdan Z. Olenyuk

Nutritional Sciences and Wellness, Research

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

81 Scopus citations

Abstract

Selective blockade of hypoxia-inducible gene expression by designed small molecules would prove valuable in suppressing tumor angiogenesis, metastasis and altered energy metabolism. We report the design, synthesis, and biological evaluation of a dimeric epidithiodiketopiperazine (ETP) small molecule transcriptional antagonist targeting the interaction of the p300/CBP coactivator with the transcription factor HIF-1R. Our results indicate that disrupting this interaction results in rapid downregulation of hypoxiainducible genes critical for cancer progression. The observed effects are compound-specific and dosedependent. Controlling gene expression with designed small molecules targeting the transcription factorcoactivator interface may represent a new approach for arresting tumor growth.

Original language	English (US)
Pages (from-to)	18078-18088
Number of pages	11
Journal	Journal of the American Chemical Society
Volume	131
Issue number	50
DOIs	https://doi.org/10.1021/ja807601b
State	Published - Dec 23 2009

ASJC Scopus subject areas

Catalysis
General Chemistry
Biochemistry
Colloid and Surface Chemistry

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Block, K. M., Wang, H., Szabó, L. Z., Polaske, N. W., Henchey, L. K., Dubey, R., Kushal, S., László, C. F., Makhoul, J., Song, Z., Meuillet, E. J., & Olenyuk, B. Z. (2009). Direct inhibition of hypoxia-inducible transcription factor complex with designed dimeric epidithiodiketopiperazine. Journal of the American Chemical Society, 131(50), 18078-18088. https://doi.org/10.1021/ja807601b

Block, KM, Wang, H, Szabó, LZ, Polaske, NW, Henchey, LK, Dubey, R, Kushal, S, László, CF, Makhoul, J, Song, Z, Meuillet, EJ & Olenyuk, BZ 2009, 'Direct inhibition of hypoxia-inducible transcription factor complex with designed dimeric epidithiodiketopiperazine', Journal of the American Chemical Society, vol. 131, no. 50, pp. 18078-18088. https://doi.org/10.1021/ja807601b

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AU - Henchey, Laura K.

AU - Dubey, Ramin

AU - Kushal, Swati

AU - László, Csaba F.

AU - Makhoul, Joshua

AU - Song, Zuohe

AU - Meuillet, Emmanuelle J.

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AB - Selective blockade of hypoxia-inducible gene expression by designed small molecules would prove valuable in suppressing tumor angiogenesis, metastasis and altered energy metabolism. We report the design, synthesis, and biological evaluation of a dimeric epidithiodiketopiperazine (ETP) small molecule transcriptional antagonist targeting the interaction of the p300/CBP coactivator with the transcription factor HIF-1R. Our results indicate that disrupting this interaction results in rapid downregulation of hypoxiainducible genes critical for cancer progression. The observed effects are compound-specific and dosedependent. Controlling gene expression with designed small molecules targeting the transcription factorcoactivator interface may represent a new approach for arresting tumor growth.

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Direct inhibition of hypoxia-inducible transcription factor complex with designed dimeric epidithiodiketopiperazine

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