Discovery of a dual PROTAC for degrading WDR5 and Ikaros oncoproteins as therapeutics [RNA-Seq]

WD repeat domain 5 (WDR5), a chromatin regulator associated with MLL complex and MYC oncoproteins, was shown to be critical for oncogenesis in human cancers and represents an attractive drug target. Inhibitors for targeting protein-protein interaction interfaces (PPIs) within WDR5 were developed; however, they inhibited only a part of WDR5-mediated functional interactions, exerting rather limited antitumor effects. We report a cereblon (CRBN)-based proteolysis targeting chimera (PROTAC) of WDR5, MS40, which is capable of selectively degrading cellular WDR5 and well-established imide:CRBN targets such as Ikaros (IKZF1). MS40-induced WDR5 degradation caused disassociation of MLL complex off chromatin, resulting in a decrease of global H3K4me2. Transcriptomic profiling also revealed targets of both WDR5 and imide:CRBN to be repressed by MS40. In MLL-rearranged acute leukemias, which exhibit high IKZF1 expression and IKZF1 dependency, co-suppression of WDR5 and IKZF1/3 by MS40 is superior at suppressing tumor growth not only to WDR5 PPI inhibitors but also to a VHL-based WDR5 PROTAC, MS169, which selectively targets WDR5 only. Furthermore, MS40 suppressed growth of primary leukemia patient cells in vitro and patient-derived xenografts (PDX) in vivo. Collectively, we report the discovery of a dual WDR5 and Ikaros degrader as anti-cancer therapeutic. Overall design: Examination of transcriptome profiles using the MV4;11 cells treated with either DMSO, MS40 (a WDR5 and Ikaros degrader), MS40N1 (an E3-“dead” analog of MS40) or pomalidomide, or cells transduced with a WDR5-targeting hairpin (sh#47) or vector (shEV).