Discovery of High-Affinity Small-Molecule Binders of the Epigenetic Reader YEATS4

A series of small-molecule YEATS4 binders have been discovered
as part of an ongoing research effort to generate high-quality probe
molecules for emerging and/or challenging epigenetic targets. Analogues
such as 4d and 4e demonstrate excellent
potency and selectivity for YEATS4 binding versus YEATS1,2,3 and exhibit
good physical properties and in vitro safety profiles. A new X-ray
crystal structure confirms direct binding of this chemical series
to YEATS4 at the lysine acetylation recognition site of the YEATS
domain. Multiple analogues engage YEATS4 with nanomolar potency in
a whole-cell nanoluciferase bioluminescent resonance energy transfer
assay. Rodent pharmacokinetic studies demonstrate the competency of
several analogues as in vivo-capable binders.