Advances in discovering small molecules to probe protein function in a systems context

•We review selected recent developments in chemical high-throughput screening (HTS).•Target-based HTS assays have recently been adapted for new target classes.•Cell-based HTS assays rely on the ability to define and quantify complex phenotypes.•Both strategies have yielded effective probes for studying uncharacterized biology.

High throughput screening (HTS) has historically been used for drug discovery almost exclusively by the pharmaceutical industry. Due to a significant decrease in costs associated with establishing a high throughput facility and an exponential interest in discovering probes of development and disease associated biomolecules, HTS core facilities have become an integral part of most academic and non-profit research institutions over the past decade. This major shift has led to the development of new HTS methodologies extending beyond the capabilities and target classes used in classical drug discovery approaches such as traditional enzymatic activity-based screens. In this brief review we describe some of the most interesting developments in HTS technologies and methods for chemical probe discovery.