4N5T: The 1.7A Crystal Structure of MDMX with a Stapled Peptide, ATSP-7041

Citation:
Abstract
Stapled alpha-helical peptides have emerged as a promising new modality for a wide range of therapeutic targets. Here, we report a potent and selective dual inhibitor of MDM2 and MDMX, ATSP-7041, which effectively activates the p53 pathway in tumors in vitro and in vivo. Specifically, ATSP-7041 binds both MDM2 and MDMX with nanomolar affinities, shows submicromolar cellular activities in cancer cell lines in the presence of serum, and demonstrates highly specific, on-target mechanism of action. A high resolution (1.7-A) X-ray crystal structure reveals its molecular interactions with the target protein MDMX, including multiple contacts with key amino acids as well as a role for the hydrocarbon staple itself in target engagement. Most importantly, ATSP-7041 demonstrates robust p53-dependent tumor growth suppression in MDM2/MDMX-overexpressing xenograft cancer models, with a high correlation to on-target pharmacodynamic activity, and possesses favorable pharmacokinetic and tissue distribution properties. Overall, ATSP-7041 demonstrates in vitro and in vivo proof-of-concept that stapled peptides can be developed as therapeutically relevant inhibitors of protein-protein interaction and may offer a viable modality for cancer therapy.
PDB ID: 4N5TDownload
MMDB ID: 115344
PDB Deposition Date: 2013/10/10
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 1.7  Å
Source Organism:
Danio rerio
Similar Structures:
Biological Unit for 4N5T: dimeric; determined by author and by software (PISA)
Molecular Components in 4N5T
Label Count Molecule
Proteins (2 molecules)
1
Protein Mdm4(Gene symbol: mdm4)
Molecule annotation
1
Atsp-7041 Stapled-peptide
Molecule annotation
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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