Journal
CHEMMEDCHEM
Volume 13, Issue 5, Pages 406-410Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201700749
Keywords
antitumor agents; Bcl-2 transcriptional down-regulation; gene promoters; G-quadruplexes; ligands
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Funding
- Italian Association for Cancer Research (AIRC) [IG16730, IG18695, MFAG 18793]
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Targeting of G-quadruplex-forming DNA in the BCL2 gene promoter to inhibit the expression of anti-apoptotic Bcl-2 protein is an attractive approach to cancer treatment. So far, efforts made in the discovery of molecules that are able to target the BCL2 G-quadruplex have succeeded mainly in the identification of ligands with poor drug-like properties. Here, a small series of furo[2,3-d]pyridazin-4(5H)-one derivatives were evaluated as a new class of drug-like G-quadruplex-targeting compounds. Biophysical studies showed that two derivatives could effectively bind to BCL2 G-quadruplex with good selectivity. Moreover, one such ligand was found to appreciably inhibit BCL2 gene transcription, with a substantial decrease in protein expression levels, and also showed significant cytotoxicity toward the Jurkat human T-lymphoblastoid cell line.
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