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

A. Romanelli; G. Stazi; R. Fioravanti; C. Zwergel; E. Di Bello; S. Pomella; C. Perrone; C. Battistelli; R. Strippoli; M. Tripodi; D. Del Bufalo; R. Rota; D. Trisciuoglio; A. Mai; S. Valente

doi:10.1021/acsmedchemlett.0c00014

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

A. Romanelli, G. Stazi, R. Fioravanti, C. Zwergel, E. Di Bello, S. Pomella, C. Perrone, C. Battistelli, R. Strippoli, M. Tripodi, D. Del Bufalo, R. Rota, D. Trisciuoglio, A. Mai, S. Valente

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. © 2020 American Chemical Society.

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

Keywords

anticancer agent
Drug discovery
dual-target inhibitor
histone deacetylase
histone methyltransferase
alpha tubulin
antineoplastic agent
histone deacetylase inhibitor
transcription factor EZH2
uvomorulin
alveolar rhabdomyosarcoma cell line
Article
biological activity
cancer cell
cell differentiation
cell viability
controlled study
drug design
drug screening
epithelial mesenchymal transition
G1 phase cell cycle checkpoint
glioblastoma cell line
human
human cell
priority journal
protein expression
U-937 cell line

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10.1021/acsmedchemlett.0c00014

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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. ACS Med. Chem. Lett., 11(5), 977-983. https://doi.org/10.1021/acsmedchemlett.0c00014

Design of First-in-Class Dual EZH2/HDAC Inhibitor: Biochemical Activity and Biological Evaluation in Cancer Cells : ACS Medicinal Chemistry Letters. / 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.

In: ACS Med. Chem. Lett., Vol. 11, No. 5, 2020, p. 977-983.

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

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', ACS Med. Chem. Lett., vol. 11, no. 5, pp. 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. / Design of First-in-Class Dual EZH2/HDAC Inhibitor: Biochemical Activity and Biological Evaluation in Cancer Cells : ACS Medicinal Chemistry Letters. In: ACS Med. Chem. Lett. 2020 ; Vol. 11, No. 5. pp. 977-983.

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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. {\textcopyright} 2020 American Chemical Society.",

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author = "A. Romanelli and G. Stazi and R. Fioravanti and C. Zwergel and {Di Bello}, E. and S. Pomella and C. Perrone and C. Battistelli and R. Strippoli and M. Tripodi and {Del Bufalo}, D. and R. Rota and D. Trisciuoglio and A. Mai and S. Valente",

note = "Cited By :8 Export Date: 19 March 2021 CODEN: AMCLC Correspondence Address: Mai, A.; Department of Drug Chemistry and Technologies, P. le A. Moro 5, Italy; email: antonello.mai@uniroma1.it Correspondence Address: Valente, S.; Department of Drug Chemistry and Technologies, P. le A. Moro 5, Italy; email: sergio.valente@uniroma1.it Correspondence Address: Rota, R.; Department of Oncohematology, Viale San Paolo 15, Italy; email: rossella.rota@opbg.net Correspondence Address: Trisciuoglio, D.; Preclinical Models and New Therapeutic Agents Unit, Viale Regina Elena 291, 295, Italy; email: daniela.trisciuoglio@uniroma1.it",

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language = "English",

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T2 - ACS Medicinal Chemistry Letters

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AU - Stazi, G.

AU - Fioravanti, R.

AU - Zwergel, C.

AU - Di Bello, E.

AU - Pomella, S.

AU - Perrone, C.

AU - Battistelli, C.

AU - Strippoli, R.

AU - Tripodi, M.

AU - Del Bufalo, D.

AU - Rota, R.

AU - Trisciuoglio, D.

AU - Mai, A.

AU - Valente, S.

N1 - Cited By :8 Export Date: 19 March 2021 CODEN: AMCLC Correspondence Address: Mai, A.; Department of Drug Chemistry and Technologies, P. le A. Moro 5, Italy; email: antonello.mai@uniroma1.it Correspondence Address: Valente, S.; Department of Drug Chemistry and Technologies, P. le A. Moro 5, Italy; email: sergio.valente@uniroma1.it Correspondence Address: Rota, R.; Department of Oncohematology, Viale San Paolo 15, Italy; email: rossella.rota@opbg.net Correspondence Address: Trisciuoglio, D.; Preclinical Models and New Therapeutic Agents Unit, Viale Regina Elena 291, 295, Italy; email: daniela.trisciuoglio@uniroma1.it

PY - 2020

Y1 - 2020

N2 - 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. © 2020 American Chemical Society.

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. © 2020 American Chemical Society.

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KW - Drug discovery

KW - dual-target inhibitor

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KW - histone methyltransferase

KW - alpha tubulin

KW - antineoplastic agent

KW - histone deacetylase inhibitor

KW - transcription factor EZH2

KW - uvomorulin

KW - alveolar rhabdomyosarcoma cell line

KW - Article

KW - biological activity

KW - cancer cell

KW - cell differentiation

KW - cell viability

KW - controlled study

KW - drug design

KW - drug screening

KW - epithelial mesenchymal transition

KW - G1 phase cell cycle checkpoint

KW - glioblastoma cell line

KW - human

KW - human cell

KW - priority journal

KW - protein expression

KW - U-937 cell line

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DO - 10.1021/acsmedchemlett.0c00014

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SP - 977

EP - 983

JO - ACS Med. Chem. Lett.

JF - ACS Med. Chem. Lett.

SN - 1948-5875

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ER -