Affinity-based protein profiling of MDM2 inhibitor Navtemadlin
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Navtemadlin is a potent inhibitor of the p53-MDM2 protein–protein interaction, which plays a critical role in the proliferation of p53-wildtype tumours. Whilst Navtemadlin has progressed to multiple Phase III clinical trials in oncology, little has been disclosed regarding its selectivity for MDM2 in cells. Here, we report the synthesis and validation of photoactivatable clickable probes of Navtemadlin, and their application to de novo target discovery for Navtemadlin through affinity-based protein profiling. MDM2 was robustly identified as the main target, across two cell lines, using two distinct probe designs. While off-targets were identified, these were not consistent across cell lines and probe designs, consistent with a high degree of selectivity for the target protein. Whole proteome profiling experiments across different time points confirmed p53-mediated phenotypic activity and revealed novel expression patterns for key proteins in the p53 pathway.
Date Issued
2025-04-28
Date Acceptance
2025-03-07
Citation
Chemical Science, 2025, 16, pp.6886-6894
ISSN
2041-6520
Publisher
The Royal Society of Chemistry
Start Page
6886
End Page
6894
Journal / Book Title
Chemical Science
Volume
16
Copyright Statement
© 2025 The Author(s). Published by the Royal Society of Chemistry. This article is licensed under aCreative Commons Attribution 3.0 Unported Licence.View Article OnlineView Journal| View Issue
License URL
Identifier
10.1039/d5sc00120j
Publication Status
Published
Date Publish Online
2025-03-12