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

ABSTRACT:

Background

Targeting ribosome biogenesis to activate p53 has recently emerged as a therapeutic strategy in human cancer. Among various ribosomal proteins, RPL11 centralizes the nucleolar stress-sensing pathway by binding MDM2, leading to MDM2 inactivation and p53 activation. Therefore, the identification of MDM2-binding RPL11-mimetics would be valuable for anti-cancer therapeutics.

Methods

Based on the crystal structure of the interface between RPL11 and MDM2, we have identified 15 potential allosteric modulators of MDM2 through the virtual screening.

Results

One of these compounds, named S9, directly binds MDM2 and competitively inhibits the interaction between RPL11 and MDM2, leading to p53 stabilization and activation. Moreover, S9 inhibits cancer cell proliferatio

SUBMITTER: Wang B 

PROVIDER: S-EPMC9450376 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature