Discovery, X-ray structure and CPP-conjugation enabled uptake of p53/MDM2 macrocyclic peptide inhibitors

• DOI: 10.1039/d1cb00056j
• Publication Date: 2021-08-26T15:41:09Z
• Authors: Anselm F. L. Schn...; Joerg Kallen; Johannes Ottl; Patrick C. Reid; Sebastien Ripoche; Stephan Ruetz; Therese-Marie Sta...; Samuel Hintermann; Christoph E. Dumelin; Christian P. R. H...; Andreas L. Marzinzik
• Keywords: Cyclic peptide

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 library >1012in vitro-translated cyclic peptides, we have identified macrocyclic ligand that shows picomolar potency on MDM2. X-Ray crystallography reveals novel binding mode utilizing unique pharmacophore occupy Phe/Trp/Leu pockets Conjugation cell-penetrating peptide (cCPP) initially non cell-permeable enables cellular uptake and pharmacodynamic response in SJSA-1 cells. The demonstrated enhanced intracellular availability peptides are by technology exemplifies process for application tools drug discovery projects.