Design, Synthesis, Biophysical and Structure-Activity Properties of a Novel Dual MDM2 and MDMX Targeting Stapled α-Helical Peptide: ATSP-7041 Exhibits Potent In Vitro and In Vivo Efficacy in Xenograft Models of Human Cancer

摘要

Activation of the p53 tumor suppressor protein by disrupting its interactions with both MDM2 and MDMX provides an opportunity for the development of a novel cancer therapeutic to treat p53 wild-type tumors. Stapled Peptides are a breakthrough approach to create a new class of drugs that target intracellular protein-protein interactions [1,2]. Here, we describe the stapled a-helical peptide ATSP-7041, a novel dual inhibitor of MDM2 and MDMX that reactivates p53-dependent pathway in multiple cancer cell lines in vitro and in vivo.