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

2013; National Academy of Sciences; Volume: 110; Issue: 36 Linguagem: Inglês

10.1073/pnas.1303002110

1091-6490

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

Ubiquitin and proteasome pathways

Significance Stapled α−helical peptides have emerged as a promising new modality for a wide range of therapeutic targets. Here, we describe the development of a stapled α−helical peptide lead molecule for the treatment of cancers that possess the intact p53 tumor suppressor protein but are resistant to drug therapy because of the overexpression of inhibitory proteins MDM2 and MDMX. The molecule ATSP-7041 is a highly potent dual inhibitor of both MDM2 and MDMX that is shown to effectively reactivate the p53 tumor suppressor pathway in a mechanism-dependent manner in p53-positive cancers in vitro and in vivo.