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.
Journal article
Journal of medicinal chemistry
01/2023
66
460 - 472
Pfizer Medicine Design, Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139, United States.
Gene Expression Regulation, Epigenesis, Genetic, Protein Processing, Post-Translational, Acetylation, Protein Domains