Discovery of High-Affinity Small-Molecule Binders of the Epigenetic Reader YEATS4.
Allyn T LondreganKarlygash AitmakhanovaJames BennettLaura J ByrnesDaniel P CanterburyXiayun ChengThomas ChristottJennifer ClemensSteven B CoffeyJoão M DiasMatthew S DowlingGillian FarnieOleg FedorovKimberly F FennellVicki GambleCarina GileadiCharline GiroudMichael R HarrisBrett D HollingsheadKilian V M HuberMagdalena KorczynskaKimberly LaphamPaula M LoriaArjun NarayananDafydd R OwenBrigitt RauxParag V SahasrabudheRoger B RuggeriLaura Díaz SáezIngrid A StockBenjamin A ThumaAndy TsaiAlison E VarghesePublished in: Journal of medicinal chemistry (2022)
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.
Keyphrases
- small molecule
- energy transfer
- crystal structure
- dna methylation
- molecular docking
- protein protein
- gene expression
- quantum dots
- high throughput
- mental health
- physical activity
- structure activity relationship
- stem cells
- magnetic resonance imaging
- transcription factor
- mass spectrometry
- mesenchymal stem cells
- dual energy