The WD40-repeat protein WDR5 scaffolds various epigenetic writers and is a critical component of the mammalian SET/MLL histone methyltransferase complex. Dysregulation of the MLL1 catalytic function is associated with mixed-lineage leukemia, and antagonism of the WDR5-MLL1 interaction by small molecules has been proposed as a therapeutic strategy for MLL-rearranged cancers. Small molecule binders of the "WIN" site of WDR5 that cause displacement from chromatin have been additionally implicated to be of broader use in cancer treatment. In this study, a fragment screen with Surface Plasmon Resonance (SPR) was used to identify a highly ligand-efficient imidazole-containing compound that is bound in the WIN site. The subsequent medicinal chemistry campaign-guided by a suite of high-resolution cocrystal structures with WDR5-progressed the initial hit to a low micromolar binder. One outcome from this study is a moiety that substitutes well for the side chain of arginine; a tripeptide containing one such substitution was resolved in a high resolution structure (1.5 Å) with a binding mode analogous to the native tripeptide. SPR furthermore indicates a similar residence time (k d = ∼0.06 s-1) for these two analogs. This novel scaffold therefore represents a possible means to overcome the potential permeability issues of WDR5 ligands that possess highly basic groups like guanidine. The series reported here furthers the understanding of the WDR5 WIN site and functions as a starting point for the development of more potent WDR5 inhibitors that may serve as cancer therapeutics.

中文翻译：

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用于WDR5的蛋白质​​-蛋白质相互作用抑制剂的片段筛选。

WD40重复蛋白WDR5支撑各种表观遗传学作者，并且是哺乳动物SET / MLL组蛋白甲基转移酶复合物的重要组成部分。MLL1催化功能的失调与混合谱系白血病有关，并且已经提出了通过小分子拮抗WDR5-MLL1相互作用作为MLL重排癌症的治疗策略。WDR5的“ WIN”位点的小分子结合剂可导致从染色质的移位，另外还被认为在癌症治疗中具有更广泛的用途。在这项研究中，使用具有表面等离子体共振（SPR）的片段筛选技术来鉴定结合在WIN位点的具有高配体效率的含咪唑的化合物。随后的药物化学运动由一系列带有WDR5的高分辨率共晶结构引导，使最初的打击成为了低微摩尔粘合剂。这项研究的结果之一是可以很好地替代精氨酸侧链的部分。含有一个这样的取代基的三肽以类似于天然三肽的结合模式解析为高分辨率结构（1.5）。SPR还表明这两个类似物的停留时间相似（kd =〜0.06 s-1）。因此，这种新颖的支架代表了一种可能的方法，可以克服具有高碱性基团（如胍）的WDR5配体的潜在渗透性问题。