Journal Article

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

Chang, Yong S., Horstick, James, Nash, Huw, Berry, Pamela, Qureshi, Farooq Z., Olson, Karen A., To, Kwong-Him, Graves, Bradford, Kesavan, Kamala, Manning, Anthony M., Baker, Theresa, Feyfant, Eric, Packman, Kathryn, Cai, Hongliang, Guerlavais, Vincent, Vassilev, Lyubomir T., Filipovic, Zoran, Tovar, Christian, Fotouhi, Nader, Elkin, Carl, Gangurde, Pranoti, Sawyer, Tomi K., Annis, D. Allen, Darlak, Krzysztof, Mukherjee, Aditi, Shi, Xiangguo E.

2013

Overview

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-Å) 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.

• Publisher: National Academy of Sciences
• Subject: amino acids / Animals / Antineoplastic Agents - chemistry / Antineoplastic Agents - pharmacokinetics / Antineoplastic Agents - therapeutic use / Area Under Curve / Binding, Competitive / Biological Sciences / blood serum / Cell Line, Tumor / Chemistry / Crystallography, X-Ray / drugs / Female / HCT116 Cells / Humans / Male / MCF-7 Cells / mechanism of action / Mice / Mice, Nude / Models, Molecular / neoplasms / Neoplasms - drug therapy / Neoplasms - metabolism / Neoplasms - pathology / peptides / Peptides - chemistry / Peptides - metabolism / Peptides - therapeutic use / Peptides, Cyclic - chemistry / Peptides, Cyclic - pharmacokinetics / Peptides, Cyclic - therapeutic use / pharmacokinetics / Pharmacology / Physical Sciences / PNAS Plus / Protein Binding / Protein Conformation / Protein Structure, Secondary / protein-protein interactions / Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors / Proto-Oncogene Proteins c-mdm2 - metabolism / Rats / Rats, Long-Evans / therapeutics / tissue distribution / Tumor Suppressor Protein p53 - metabolism / X-ray diffraction / Xenograft Model Antitumor Assays