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@article{Date:2025:10.1039/D5SC00120J,
author = {Date, A and Wall, A and Zhang, P and Houghton, J and Lu, J and Thomas, A and Kovacic, T and Wilson, A and Tate, E and Barnard, A},
doi = {10.1039/D5SC00120J},
journal = {Chemical Science},
pages = {6886--6894},
title = {Affinity-based protein profiling of MDM2 inhibitor Navtemadlin},
url = {http://dx.doi.org/10.1039/D5SC00120J},
volume = {16},
year = {2025}
}
TY - JOUR
AB - 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.
AU - Date,A
AU - Wall,A
AU - Zhang,P
AU - Houghton,J
AU - Lu,J
AU - Thomas,A
AU - Kovacic,T
AU - Wilson,A
AU - Tate,E
AU - Barnard,A
DO - 10.1039/D5SC00120J
EP - 6894
PY - 2025///
SN - 2041-6520
SP - 6886
TI - Affinity-based protein profiling of MDM2 inhibitor Navtemadlin
T2 - Chemical Science
UR - http://dx.doi.org/10.1039/D5SC00120J
VL - 16
ER -
Prof. Ed Tate
GSK Chair in Chemical Biology
Department of Chemistry
Molecular Sciences Research Hub, White City Campus,
82 Wood Lane, London, W12 0BZ
e.tate@imperial.ac.uk
Tel: +44 (0)20 759 + ext 43752 or 45821