Hot-spot guided design of macrocyclic inhibitors of the LSD1-CoREST1 interaction

Abstract

New modalities such as cyclic peptides are attractive structures to inhibit challenging targets. The interaction between LSD1 and CoREST1 is required for histone demethylation and represents an attractive therapeutic target. The large interaction surface between these two proteins was analyzed by virtual alanine scanning using DrugScore PPI and a cluster of hot-spot residues was identified on CoREST1. The cluster was converted into a series of cyclic peptides and the inhibitory potency was optimized by stereochemical inversion at one of the amino acids alpha carbons combined with modification of amino acid side chains. Active peptides were further studied by variable temperature 1H NMR and docking to evaluate the effect of conformation on binding. Potent inhibitors of the challenging PPI were obtained and will allow future optimization into more druglike structures.