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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.

Original publication

DOI

10.1021/acs.jmedchem.2c01421

Type

Journal article

Journal

J Med Chem

Publication Date

12/01/2023

Volume

66

Pages

460 - 472

Keywords

Gene Expression Regulation, Protein Domains, Acetylation, Protein Processing, Post-Translational, Epigenesis, Genetic