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.

中文翻译：

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使用新型基于呋喃哒嗪酮的分子靶向BCL2基因启动子G-四链体

针对BCL2基因启动子中形成G四链体的DNA抑制抗凋亡Bcl-2蛋白的表达是治疗癌症的一种有吸引力的方法。到目前为止，发现能够靶向BCL2 G-四链体的分子所做的努力主要成功地鉴定了具有不良药物样性质的配体。在这里，一小部分的呋喃[2,3 - d ]哒嗪-4（5 H）-one衍生物被评估为一类新的药物样G-四链体靶向化合物。生物物理研究表明，两种衍生物可以有效结合BCL2 G-四链体，并具有良好的选择性。此外，发现一种这样的配体可明显抑制BCL2 基因转录，蛋白质表达水平显着下降，并且还显示出对Jurkat人T淋巴母细胞样细胞系的显着细胞毒性。