Development of cell‐penetrating peptide‐based drug leads to inhibit MDMX:p53 and MDM2:p53 interactions

Grégoire Philippe, Yen‐Hua Huang, Olivier Cheneval, Nicole Lawrence, Zhen Zhang, David P Fairlie, David J. Craik, Aline Dantas de Araujo, Sónia Troeira Henriques

The transcription factor p53 has a tumor suppressor role in leading damaged cells to apoptosis. Its activity is regulated/inhibited in healthy cells by the proteins MDM2 and MDMX. Overexpression of MDM2 and/or MDMX in cancer cells inactivates p53, facilitating tumor development. A 12-mer dual inhibitor peptide (pDI) was previously reported to be able to target and inhibit MDMX:p53 and MDM2:p53 interactions with nanomolar potency in vitro. With the aim of improving its cellular inhibitory activity, we produced a series of constrained pDI analogues featuring lactam staples that stabilize the bioactive helical conformation and fused them with a cell-penetrating peptide to increase cytosol delivery. We compared pDI and its analogues on their inhibitory potency, toxicity and ability to enter cancer cells. Overall, the results show that these analogues keep their nanomolar affinity for MDM2 and MDMX and are highly active against cancer cells. This article is protected by copyright. All rights reserved.