Abstract

Macrocyclic compounds are an attractive modality for drug development because their shape and composition allows binding to challenging disease targets that are "undruggable" by classical small molecules. However, the development of macrocyclic ligands to targets of interest is currently difficult due to the lack of sufficiently large libraries that can be screened. To address this limitation, my laboratory has developed a technology for synthesizing and screening large combinatorial libraries of small macrocyclic compounds. In brief, we combinatorially synthesize macrocycles in microwell plates at a nanomole scale using acoustic liquid transfer for reagent and building block transfer. Omission of a purification step allowed us to generate and screen large libraries of ten-thousands of compounds, and to find binders to a range of targets, including a protein-protein interaction. A small size (< 600 Da) and a limited polar surface allows macrocycles of this type crossing membranes and thus accessing intracellular targets, which makes them attractive for drug development.