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

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.