A High-Throughput Cell-Based Screen Identified a 2-[(E)-2-Phenylvinyl]-8-Quinolinol Core Structure That Activates p53

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• p53 tumor suppressor function is often lost in cancer via mutation or degradation by MDM2/E6AP.
• Existing therapies primarily aim to prevent p53 degradation, with fewer compounds directly activating p53.
• Restoring p53 activity is a key strategy for developing novel anti-cancer agents.

Purpose of the Study:

• To identify novel compounds that directly bind to and activate p53.
• To develop a new cell-based high-throughput screen for p53-activating compounds.
• To characterize the mechanism of action and anti-cancer potential of identified compounds.

Main Methods:

• Developed a novel cell-based screen to redirect p53 degradation to the SCF ubiquitin ligase complex.
• Utilized a multiplexed assay coupling p53 and Rb1 degradation for compound screening.
• Employed surface plasmon resonance to confirm p53 binding affinity (KD of 200 ± 52 nM).

Main Results:

• Identified a 2-[(E)-2-phenylvinyl]-8-quinolinol core structure that stabilizes p53.
• Compounds increased p53 nuclear localization and transcription of target genes (PUMA, BAX, p21, FAS).
• Compounds inhibited cancer cell proliferation, with some effects observed even in p53-null cells.

Conclusions:

• A novel screening method successfully identified p53-activating compounds with a 2-[(E)-2-phenylvinyl]-8-quinolinol core.
• These compounds demonstrate potential as anti-neoplastic agents by stabilizing p53 and potentially engaging other pathways.
• Further research into these compounds could lead to new cancer treatment strategies targeting p53.