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Open AccessArticle

Novel Quinoline Compounds Active in Cancer Cells through Coupled DNA Methyltransferase Inhibition and Degradation

1
Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy
2
Department of Precision Medicine, University of Studi della Campania Luigi Vanvitelli, Vico L. De Crecchio 7, 80138 Naples, Italy
3
Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
4
Research Institute for Medicines, Medicinal Chemistry Group, Faculty of Pharmacy, Universidade de Lisboa, 1649 003 Lisbon, Portugal
5
National Institute for Infectious Diseases L. Spallanzani, IRCCS, Via Portuense, 292, 00149 Rome, Italy
6
Istituto Pasteur- Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza Università di Roma, 00185 Rome, Italy
7
ETaC CNRS FRE3600, LMBE, 118 route de Narbonne, 31062 Toulouse, France
8
Epigenetic Chemical Biology, Institute Pasteur, CNRS UMR3523, 28 rue du Docteur Roux, 75724 Paris, France
9
Preclinical Models and New Therapeutic Agents Unit, IRCCS-Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy
10
Institute of Molecular Biology and Pathology, National Research Council (CNR), Via Degli Apuli 4, 00185 Rome, Italy
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2020, 12(2), 447; https://doi.org/10.3390/cancers12020447
Received: 22 December 2019 / Revised: 31 January 2020 / Accepted: 12 February 2020 / Published: 14 February 2020
(This article belongs to the Special Issue Targeting Solid Tumors)
DNA methyltransferases (DNMTs) play a relevant role in epigenetic control of cancer cell survival and proliferation. Since only two DNMT inhibitors (azacitidine and decitabine) have been approved to date for the treatment of hematological malignancies, the development of novel potent and specific inhibitors is urgent. Here we describe the design, synthesis, and biological evaluation of a new series of compounds acting at the same time as DNMTs (mainly DNMT3A) inhibitors and degraders. Tested against leukemic and solid cancer cell lines, 2a–c and 4a–c (the last only for leukemias) displayed up to submicromolar antiproliferative activities. In HCT116 cells, such compounds induced EGFP gene expression in a promoter demethylation assay, confirming their demethylating activity in cells. In the same cell line, 2b and 4c chosen as representative samples induced DNMT1 and -3A protein degradation, suggesting for these compounds a double mechanism of DNMT3A inhibition and DNMT protein degradation.
Keywords: drug discovery; medicinal chemistry; DNA methyltransferase; enzyme inhibition; protein degradation; apoptosis drug discovery; medicinal chemistry; DNA methyltransferase; enzyme inhibition; protein degradation; apoptosis
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Zwergel, C.; Fioravanti, R.; Stazi, G.; Sarno, F.; Battistelli, C.; Romanelli, A.; Nebbioso, A.; Mendes, E.; Paulo, A.; Strippoli, R.; Tripodi, M.; Pechalrieu, D.; Arimondo, P.B.; De Luca, T.; Del Bufalo, D.; Trisciuoglio, D.; Altucci, L.; Valente, S.; Mai, A. Novel Quinoline Compounds Active in Cancer Cells through Coupled DNA Methyltransferase Inhibition and Degradation. Cancers 2020, 12, 447.

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