Identification of a small-molecule RPL11 mimetic that inhibits tumor growth by targeting MDM2-p53 pathway

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Targeting ribosome biogenesis to activate p53 is a novel cancer therapeutic strategy.
• Ribosomal protein L11 (RPL11) activates p53 by binding and inhibiting MDM2, a key regulator of p53.
• Identifying MDM2-binding RPL11-mimetics is crucial for developing new anti-cancer drugs.

Purpose of the Study:

• To identify novel compounds that mimic RPL11's interaction with MDM2.
• To evaluate the anti-cancer potential of identified MDM2 modulators.

Main Methods:

• Virtual screening based on the crystal structure of the RPL11-MDM2 interface.
• In vitro and in vivo assays to assess compound efficacy and mechanism of action.

Main Results:

• Identified 15 potential MDM2 allosteric modulators.
• Compound S9 directly binds MDM2, inhibiting RPL11-MDM2 interaction, stabilizing and activating p53.
• S9 inhibits cancer cell proliferation and induces G2 cell cycle arrest and apoptosis in vitro and in vivo.

Conclusions:

• S9 acts as an MDM2 inhibitor, leading to p53 activation and anti-cancer effects.
• S9 demonstrates potential as a lead compound for developing targeted anti-cancer therapeutics.
• The RPL11-MDM2-p53 pathway is a viable target for novel cancer drug development.