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.