Stapled α-helical peptide drug development: a potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy.

Stapled α-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.
Mesh Terms:
Animals, Antineoplastic Agents, Area Under Curve, Binding, Competitive, Cell Line, Tumor, Crystallography, X-Ray, Female, HCT116 Cells, Humans, MCF-7 Cells, Male, Mice, Mice, Nude, Models, Molecular, Neoplasms, Peptides, Peptides, Cyclic, Protein Binding, Protein Conformation, Protein Structure, Secondary, Proto-Oncogene Proteins c-mdm2, Rats, Rats, Long-Evans, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays
Proc. Natl. Acad. Sci. U.S.A.
Date: Sep. 03, 2013
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