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

  • Proc Natl Acad Sci U S A. 2013 Sep 3;110(36):E3445-54. doi: 10.1073/pnas.1303002110.
Yong S Chang  1 ,  Bradford Graves ,  Vincent Guerlavais ,  Christian Tovar ,  Kathryn Packman ,  Kwong-Him To ,  Karen A Olson ,  Kamala Kesavan ,  Pranoti Gangurde ,  Aditi Mukherjee ,  Theresa Baker ,  Krzysztof Darlak ,  Carl Elkin ,  Zoran Filipovic ,  Farooq Z Qureshi ,  Hongliang Cai ,  Pamela Berry ,  Eric Feyfant ,  Xiangguo E Shi ,  James Horstick ,  D Allen Annis ,  Anthony M Manning ,  Nader Fotouhi ,  Huw Nash ,  Lyubomir T Vassilev ,  Tomi K Sawyer
Affiliations
PMID: 23946421 DOI: 10.1073/pnas.1303002110
Abstract

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.

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