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

ACS Med Chem Lett. 2020 Mar 19;11(5):977-983. doi: 10.1021/acsmedchemlett.0c00014. eCollection 2020 May 14.

Authors

Annalisa Romanelli¹, Giulia Stazi¹, Rossella Fioravanti¹, Clemens Zwergel^{1

2}, Elisabetta Di Bello¹, Silvia Pomella³, Clara Perrone³, Cecilia Battistelli⁴, Raffaele Strippoli^{4

5}, Marco Tripodi^{4

5}, Donatella Del Bufalo⁶, Rossella Rota³, Daniela Trisciuoglio^{7

6}, Antonello Mai¹, Sergio Valente¹

Affiliations

¹ Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy.
² Department of Medicine of Precision, University of Campania Luigi Vanvitelli, Via L. De Crecchio 7, 80138 Naples, Italy.
³ Department of Oncohematology, Bambino Gesù Children's Hospital, IRCCS, Viale San Paolo 15, 00146 Rome, Italy.
⁴ Department of Molecular Medicine, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy.
⁵ National Institute for Infectious Diseases L. Spallanzani, IRCCS, Via Portuense 292, 00149 Rome, Italy.
⁶ Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, Viale Regina Elena 291,295, 00100 Rome, Italy.
⁷ Institute of Molecular Biology and Pathology, National Research Council (CNR), Via Degli Apuli 4, Rome 00185, Italy.

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.

Grants and funding

R01 GM114306/GM/NIGMS NIH HHS/United States