Robotic alliance of miniaturized synthesis and screening: A case study for the identification of histone deacetylase inhibitors

Abstract

Modern drug development in preclinical pharmaceutics is based on two fundamental processes: library synthesis and screening. Usually, synthesis and screening are separated processes that need a compound storage facility as an interface. Unfortunately, compound storage is a complex process and can lead to compound degradation. For this reason, the chemical identities of found screening hits have to be reanalyzed after the biological screening to be confident. Here, we present a robotic facility that combines solid‐phase one‐bead one‐compound synthesis and screening in a unified workflow using miniaturized formats for on‐demand library synthesis. The technical proof of concept was achieved by an exemplary run that combines the solid‐phase synthesis of a hydroxamate library and the subsequent biological screening for different histone deacetylase activities using a homogeneous fluorescence assay. Compound storage and related processing steps were thus omitted in this way. Technical concepts for all necessary steps and their robotic solutions for the integration of both synthesis and screening processes in one overall workflow are shown in detail. As a result, different enzyme selective histone deacetylase inhibitors were identified using the integrated workflow.