Design of First-in-Class Dual EZH2/HDAC Inhibitor: Biochemical Activity and Biological Evaluation in Cancer Cells

Annalisa Romanelli; Giulia Stazi; Rossella Fioravanti; Clemens Zwergel; Elisabetta Di Bello; Silvia Pomella; Clara Perrone; Cecilia Battistelli; Raffaele Strippoli; Marco Tripodi; Donatella Del Bufalo; Rossella Rota; Daniela Trisciuoglio; Antonello Mai; Sergio Valente

doi:10.1021/acsmedchemlett.0c00014

Design of First-in-Class Dual EZH2/HDAC Inhibitor: Biochemical Activity and Biological Evaluation in Cancer Cells

Annalisa Romanelli, Giulia Stazi, Rossella Fioravanti, Clemens Zwergel, Elisabetta Di Bello, Silvia Pomella, Clara Perrone, Cecilia Battistelli, Raffaele Strippoli, Marco Tripodi, Donatella Del Bufalo, Rossella Rota, Daniela Trisciuoglio, Antonello Mai, Sergio Valente

Istituto Regina Elena

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

Abstract

Since the histone modifying enzymes EZH2 and HDACs control a number of epigenetic-dependent carcinogenic pathways, we designed the first-in-class dual EZH2/HDAC inhibitor 5 displaying (sub)micromolar inhibition against both targets. When tested in several cancer cell lines, the hybrid 5 impaired cell viability at low micromolar level and in leukemia U937 and rhabdomyosarcoma RH4 cells provided G1 arrest, apoptotic induction, and increased differentiation, associated with an increase of acetyl-H3 and acetyl-α-tubulin and a decrease of H3K27me3 levels. In glioblastoma U87 cells, 5 hampered epithelial to mesenchymal transition by increasing the E-cadherin expression, thus proposing itself as a useful candidate for anticancer therapy.

Original language	English
Pages (from-to)	977-983
Number of pages	7
Journal	ACS Medicinal Chemistry Letters
Volume	11
Issue number	5
DOIs	https://doi.org/10.1021/acsmedchemlett.0c00014
Publication status	Published - May 14 2020

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Romanelli, A., Stazi, G., Fioravanti, R., Zwergel, C., Di Bello, E., Pomella, S., Perrone, C., Battistelli, C., Strippoli, R., Tripodi, M., Del Bufalo, D., Rota, R., Trisciuoglio, D., Mai, A., & Valente, S. (2020). Design of First-in-Class Dual EZH2/HDAC Inhibitor: Biochemical Activity and Biological Evaluation in Cancer Cells. ACS Medicinal Chemistry Letters, 11(5), 977-983. https://doi.org/10.1021/acsmedchemlett.0c00014

Romanelli, A, Stazi, G, Fioravanti, R, Zwergel, C, Di Bello, E, Pomella, S, Perrone, C, Battistelli, C, Strippoli, R, Tripodi, M, Del Bufalo, D, Rota, R, Trisciuoglio, D, Mai, A & Valente, S 2020, 'Design of First-in-Class Dual EZH2/HDAC Inhibitor: Biochemical Activity and Biological Evaluation in Cancer Cells', ACS Medicinal Chemistry Letters, vol. 11, no. 5, pp. 977-983. https://doi.org/10.1021/acsmedchemlett.0c00014

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abstract = "Since the histone modifying enzymes EZH2 and HDACs control a number of epigenetic-dependent carcinogenic pathways, we designed the first-in-class dual EZH2/HDAC inhibitor 5 displaying (sub)micromolar inhibition against both targets. When tested in several cancer cell lines, the hybrid 5 impaired cell viability at low micromolar level and in leukemia U937 and rhabdomyosarcoma RH4 cells provided G1 arrest, apoptotic induction, and increased differentiation, associated with an increase of acetyl-H3 and acetyl-α-tubulin and a decrease of H3K27me3 levels. In glioblastoma U87 cells, 5 hampered epithelial to mesenchymal transition by increasing the E-cadherin expression, thus proposing itself as a useful candidate for anticancer therapy.",

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doi = "10.1021/acsmedchemlett.0c00014",

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AU - Romanelli, Annalisa

AU - Stazi, Giulia

AU - Fioravanti, Rossella

AU - Zwergel, Clemens

AU - Di Bello, Elisabetta

AU - Pomella, Silvia

AU - Perrone, Clara

AU - Battistelli, Cecilia

AU - Strippoli, Raffaele

AU - Tripodi, Marco

AU - Del Bufalo, Donatella

AU - Rota, Rossella

AU - Trisciuoglio, Daniela

AU - Mai, Antonello

AU - Valente, Sergio

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AB - Since the histone modifying enzymes EZH2 and HDACs control a number of epigenetic-dependent carcinogenic pathways, we designed the first-in-class dual EZH2/HDAC inhibitor 5 displaying (sub)micromolar inhibition against both targets. When tested in several cancer cell lines, the hybrid 5 impaired cell viability at low micromolar level and in leukemia U937 and rhabdomyosarcoma RH4 cells provided G1 arrest, apoptotic induction, and increased differentiation, associated with an increase of acetyl-H3 and acetyl-α-tubulin and a decrease of H3K27me3 levels. In glioblastoma U87 cells, 5 hampered epithelial to mesenchymal transition by increasing the E-cadherin expression, thus proposing itself as a useful candidate for anticancer therapy.

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DO - 10.1021/acsmedchemlett.0c00014

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JO - ACS Medicinal Chemistry Letters

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ER -

Design of First-in-Class Dual EZH2/HDAC Inhibitor: Biochemical Activity and Biological Evaluation in Cancer Cells

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