Picomole?Scale Synthesis and Screening of Macrocyclic Compound Libraries by Acoustic Liquid Transfer

Macrocyclic compounds are an attractive class of therapeutic ligands against challenging targets, such as protein–protein interactions. However, the development macrocycles drugs is hindered by lack large combinatorial macrocyclic libraries, which cumbersome, expensive, and time consuming to make, screen, deconvolute. Here, we established a strategy for synthesizing screening libraries on picomolar scale using acoustic droplet ejection combine building blocks at nanoliter volumes, reduced reaction reagent consumption, synthesis time. As proof-of-concept, assembled 2700-member target-focused library that could subsequently assay in same microtiter plates, saving need additional transfers deconvolution schemes. We screened MDM2–p53 interaction generated micromolar sub-micromolar inhibitors. Our approach based liquid transfer provides general macrocycle ligands.