Antagonism of protein–protein interactions (PPIs) with small molecules is becoming more feasible as a therapeutic approach. Successful PPI inhibitors tend to target proteins containing deep peptide-binding grooves or pockets rather than the more common large, flat protein interaction surfaces. Here, we review one of the most abundant PPI domains in the human proteome, the WD40 repeat (WDR) domain, which has a central peptide-binding pocket and is a member of the β-propeller domain-containing protein family. Recently, two WDR domain-containing proteins, WDR5 and EED, as well as other β-propeller domains have been successfully targeted by potent, specific, cell-active, drug-like chemical probes. Could WDR domains be a novel target class for drug discovery? Although the research is at an early stage and therefore not clinically validated, cautious optimism is justified, as WDR domain-containing proteins are involved in multiple disease-associated pathways. The druggability and structural diversity of WDR domain binding pockets suggest that understanding how to target this prevalent domain class will open up areas of disease biology that have so far resisted drug discovery efforts.

用小分子拮抗蛋白质-蛋白质相互作用（PPI）作为一种治疗方法变得越来越可行。成功的 PPI 抑制剂倾向于靶向含有深肽结合凹槽或口袋的蛋白质，而不是更常见的大而平坦的蛋白质相互作用表面。在这里，我们回顾了人类蛋白质组中最丰富的 PPI 结构域之一，WD40 重复 (WDR) 结构域，它具有中央肽结合袋，是含有 β-螺旋桨结构域的蛋白质家族的成员。最近，两种含有 WDR 结构域的蛋白 WDR5 和 EED 以及其他 β-螺旋桨结构域已成功地被有效、特异性、细胞活性、药物样化学探针所靶向。WDR 域能否成为药物发现的新靶标类别？尽管该研究尚处于早期阶段，因此尚未经过临床验证，但谨慎乐观是有道理的，因为含有 WDR 结构域的蛋白质涉及多种疾病相关途径。WDR 结构域结合袋的成药性和结构多样性表明，了解如何靶向这种常见的结构域类别将开辟迄今为止一直阻碍药物发现工作的疾病生物学领域。