Novel Quinoline Compounds Active in Cancer Cells through Coupled DNA Methyltransferase Inhibition and Degradation.
DNA methyltransferase
apoptosis
drug discovery
enzyme inhibition
medicinal chemistry
protein degradation
Journal
Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829
Informations de publication
Date de publication:
14 Feb 2020
14 Feb 2020
Historique:
received:
22
12
2019
revised:
31
01
2020
accepted:
12
02
2020
entrez:
21
2
2020
pubmed:
23
2
2020
medline:
23
2
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32075099
pii: cancers12020447
doi: 10.3390/cancers12020447
pmc: PMC7073229
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : FP7 Health
ID : BLUEPRINT - 282510
Organisme : NIH HHS
ID : R01GM114306
Pays : United States
Organisme : PlanCancer2014
ID : -
Organisme : NIGMS NIH HHS
ID : R01 GM114306
Pays : United States
Organisme : Ricerca Finalizzata 2013
ID : PE-2013-02355271
Organisme : VALERE: VAnvitelli per la Ricerca Program
ID : -
Organisme : Campania Regional Government FASE 2: IDEAL
ID : CUP B63D18000560007
Organisme : the Campania Regional Government Lotta alle Patologie Oncologiche
ID : -
Organisme : PRIN 2016
ID : 20152TE5PK
Organisme : Associazione Italiana per la Ricerca sul Cancro
ID : 19162, 17217, 18560
Organisme : iCURE (CUP B21c17000030007)
ID : -
Déclaration de conflit d'intérêts
The authors declare no conflict of interest.
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