Identification of 3-Phenylquinoline Derivative PQ1 as an Antagonist of p53 Transcriptional Activity

Abstract

Transcription factor p53 regulates cellular responses to environmental perturbations via the transcriptional activation of downstream target genes. Inappropriate p53 activation can trigger abnormal cellular responses, therefore leading to acute or chronic tissue damage, human developmental syndromes, and neurodegenerative diseases. Antagonists of p53 transcriptional activity provide prospective therapeutic applications and molecular probes. In this article, we identified five 3-phenylquinoline derivatives as potential p53 inhibitors through screening a chemical library consisting of 120 compounds, in which PQ1 was the most active compound. PQ1 had no effect on p53 protein levels and decreased the expression of p53 target gene p21. PQ1 thermally stabilizes the wild-type p53 protein. Further, transcriptomics confirmed that PQ1 exposure generated a similar regulatory effect to transcription profiles with a reported p53 transcriptional inhibitor pifithrin-α. However, compared to pifithrin-α, PQ1 increased the sensitivity of SW480 cells to 5FU. Taken together, PQ1 was a novel antagonist of p53 transcriptional activity. We propose that PQ1 could be developed as a chemical tool to pinpoint the physiological functions of p53 and a novel lead compound for targeting dysfunctional p53 activation.

CENPN contributes to pancreatic carcinoma progression through the MDM2-mediated p53 signaling pathway

“…Our results suggest that CENPN might regulate p53 expression through MDM2-mediated degradation. To further examine the relationship between CENPN and p53 transcriptional activity, we treated PAAD cells downregulated for CENPN with PFTα, a p53 inhibitor that inhibits its transcriptional activity by blocking its binding to DNA [43,44]. The results showed that the effect of si-CENPN on promoting apoptosis of PAAD cells was weakened after treatment with PFTα, suggesting that CENPN-mediated apoptosis in PAAD cells may be related to p53 transcriptional activity.…”