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

Clemens Zwergel, Rossella Fioravanti, Giulia Stazi, Federica Sarno, Cecilia Battistelli, Annalisa Romanelli, Angela Nebbioso, Eduarda Mendes, Alexandra Paulo, Raffaele Strippoli, Marco Tripodi, Dany Pechalrieu, Paola B. Arimondo, Teresa De Luca, Donatella Del Bufalo, Daniela Trisciuoglio, Lucia Altucci, Sergio Valente, Antonello Mai

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number447
Pages (from-to)1-20
Number of pages20
Issue number2
Publication statusPublished - Feb 2020


  • Apoptosis
  • DNA methyltransferase
  • Drug discovery
  • Enzyme inhibition
  • Medicinal chemistry
  • Protein degradation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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