Schneider, Anselm, Hackenberger, Christian, Kallen, Joerg, Ottl, Johannes, Reid, Patrick, Ripoche, Sebastien, Ruetz, Stephan, Stachyra, Therese-Marie, Hintermann, Samuel, Dumelin, Christoph and Marzinzik, Andreas (2021) Discovery, X-ray structure and CPP-conjugation enabled uptake of p53/MDM2 macrocyclic peptide inhibitors. RSC Chemical Biology. ISSN 2633-0679

Abstract

Mouse double minute 2 homolog (MDM2, Hdm2) is an important negative regulator of the tumor suppressor p53. Using a mRNA based display technique to screen a library of >1012 in vitro-translated cyclic peptides, we have identified a macrocyclic ligand that shows picomolar potency on MDM2. X-ray crystallography reveals a novel binding mode utilizing a unique pharmacophore to occupy the Phe/Trp/Leu pockets on MDM2. Conjugation of a cyclic cell-penetrating peptide (cCPP) to the initially non cell-permeable ligand enables cellular uptake and a pharmacodynamic response in SJSA-1 cells. The demonstrated enhanced intracellular availability of cyclic peptides that are identified by a display technology exemplifies a process for the application of intracellular tools for drug discovery projects.

Item Type:	Article
Date Deposited:	19 Oct 2021 00:45
Last Modified:	19 Oct 2021 00:45
URI:	https://oak.novartis.com/id/eprint/44434