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.

Novel quinoline compounds active in cancer cells through coupled DNA methyltransferase inhibition and degradation / 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.. - In: CANCERS. - ISSN 2072-6694. - 12:2(2020). [10.3390/cancers12020447]

Novel quinoline compounds active in cancer cells through coupled DNA methyltransferase inhibition and degradation

Zwergel C.;Fioravanti R.;Stazi G.;Battistelli C.;Romanelli A.;Mendes E.;Strippoli R.;Tripodi M.;Valente S.;Mai A.
2020

Abstract

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.
2020
Apoptosis; DNA methyltransferase; Drug discovery; Enzyme inhibition; Medicinal chemistry; Protein degradation
01 Pubblicazione su rivista::01a Articolo in rivista
Novel quinoline compounds active in cancer cells through coupled DNA methyltransferase inhibition and degradation / 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.. - In: CANCERS. - ISSN 2072-6694. - 12:2(2020). [10.3390/cancers12020447]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1364390
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