| Summary: | The aggressive nature of the activated B cell such as (ABC) subtype of diffuse large B cell (DLBCL) is frequently associated with altered B cell Receptor (BCR) signaling through the activation of key components including the scaffolding protein, <i>CARD11</i>. Most inhibitors, such as ibrutinib, target downstream BCR kinases with often modest and temporary responses for DLBCL patients. Here, we pursue an alternative strategy to target the BCR pathway by leveraging a novel DNA secondary structure to repress transcription. We discovered that a highly guanine (G)-rich element within the <i>CARD11</i> promoter forms a stable G-quadruplex (G4) using circular dichroism and polymerase stop biophysical techniques. We then identified a small molecule, naptho(2,1-b)furan-1-ethanol,2-nitro- (NSC373981), from a fluorescence-resonance energy transfer-based screen that stabilized <i>CARD11</i> G4 and inhibited <i>CARD11</i> transcription in DLBCL cells. In generating and testing analogs of NSC373981, we determined that the nitro group is likely essential for the downregulation of <i>CARD11</i> and interaction with <i>CARD11</i> G4, and the removal of the ethanol side chain enhanced this activity. Of note, the expression of <i>BCL2</i> and <i>MYC</i>, two other key oncogenes in DLBCL pathology with known promoter G4 structures, were often concurrently repressed with NSC373981 and the highly potent <b>R158</b> analog. Our findings highlight a novel approach to treat aggressive DLBCL by silencing <i>CARD11</i> gene expression that warrants further investigation.
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