Abstract

Fragment-based
drug discovery (FBDD) relies on sensitive high-throughput screening technologies
to quickly and reliably generate hits against a target. MST is a recently
established biophysical method for measuring the binding of small molecules to
a macromolecule. MST is sensitive, solution-based, low-consumption and
relatively high-throughput, making it ideal for the screening of low molecular
weight fragments against a target of interest. Here, we present a successfully
conducted MST-based fragment screen against the immuno-oncology target
indoleamine 2,3-dioxygenase 1 (IDO1).

Beginning from initial
spot-tests and confirmatory follow-up experiments we used MST to measure the
affinities for multiple fragment classes against IDO1. Half of these hits
showed inhibition in an orthogonal biochemical activity assay which revealed
potency as well as affinity. Near-neighbour SAR-by-library work further
validated the fragment hits and the MST screening approach as a whole.