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Targeting the BCL2 Gene Promoter G‐Quadruplex with a New Class of Furopyridazinone‐Based Molecules
Author(s) -
Amato Jussara,
Pagano Alessia,
Capasso Domenica,
Di Gaetano Sonia,
Giustiniano Mariateresa,
Novellino Ettore,
Randazzo Antonio,
Pagano Bruno
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700749
Subject(s) - jurkat cells , g quadruplex , gene , chemistry , small molecule , dna , transcription (linguistics) , promoter , cytotoxicity , gene expression , ligand (biochemistry) , drug discovery , computational biology , microbiology and biotechnology , biology , biochemistry , genetics , in vitro , t cell , receptor , linguistics , immune system , philosophy
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(5 H )‐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.