Efficient Solution Phase Synthesis of PPII Helix Mimicking Ena/VASP EVH1 Inhibitors from Proline‐Derived Modules (ProMs)

In the search for efficient inhibitors enabled/ vasodilator stimulated phosphoprotein homology 1 (EVH1) domain to reduce cell motility in metastatic cancer, we previously developed a toolkit of proline derived modules (ProMs), which mimic PPII helix found natural -FPPPP- binding motif EVH1. this work, describe modular assembly these ProM-based penta­peptidic EVH1 ligands through liquid phase peptide synthesis. We initially used pentafluorophenyl (Pfp) active esters amide bond formation and built up growing chain from C- N-terminus. Switching HATU/DIPEA coupling conditions changing directionality synthesis N- C-terminus afforded target with improved overall yields purity. Employing Fmoc-protected (instead N-acetylated) phenylalanine derivative as N-terminal building block significantly reduced epimerization. contrast originally solid (SPPS), solution method allowed facile alteration C-terminal ProM unit production various pentapeptidic an fashion even on multigram scale.