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.

一系列小分子YEATS4结合剂已被发现，作为当前持续推进的研究工作的一部分，旨在针对新兴及/或具有挑战性的表观遗传靶点开发高质量探针分子。诸如4d、4e的化合物类似物，相较于YEATS1、2、3，对YEATS4结合展现出优异的活性与选择性，同时具备良好的物理性质与体外安全谱。一项全新的X射线晶体结构证实，该化学系列化合物可在YEATS结构域的赖氨酸乙酰化识别位点直接结合YEATS4。多种类似物在全细胞纳米萤光素酶生物发光共振能量转移检测中，以纳摩尔级活性靶向结合YEATS4。啮齿类动物药代动力学研究证实，多款类似物具备可作为体内可用结合剂的潜力。