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

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

Affiliation

  • 1 Aileron Therapeutics, Inc., Cambridge, MA 02139, USA. ychang@aileronrx.com
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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