Disease Association and Druggability of WD40 Repeat Proteins.

WD40 repeat (WDR) domains are protein interaction scaffolds that represent one of the largest protein families in human, and a first WDR inhibitor-an allosteric antagonist of polycomb repressive complex 2-just entered the clinic. A systematic analysis of the CORUM database of protein complexes shows that WDR is the most represented domain in transcriptional regulation and one of the most prevalent in the ubiquitin proteasome system, two pathways of high relevance to drug discovery. Parsing the literature and the vulnerability of cancer cell lines to CRISPR knockout indicates that WDR proteins are targets of interest in oncology and other disease areas. A quantitative analysis of WDR structures reveals that druggable binding pockets can be found on multiple surfaces of these multifaceted protein interaction platforms. These data support the development of chemical probes to further interrogate WDR proteins as an emerging therapeutic target class.