WD repeat domain 5 (WDR5), an integral component of the MLL/KMT2A
lysine methyltransferase complex, is critically involved in
oncogenesis and represents an attractive onco-target. Inhibitors targeting
protein-
protein interactions (PPIs) between WDR5 and its binding partners, however, do not inhibit all of WDR5-mediated oncogenic functions and exert rather limited antitumor effects. Here, we report a cereblon (CRBN)-recruiting
proteolysis targeting chimera (
PROTAC) of WDR5, MS40, which selectively degrades WDR5 and the well-established neo-substrates of
immunomodulatory drugs (
IMiDs):CRBN, the Ikaros zinc finger (IKZF)
transcription factors IKZF1 and IKZF3. MS40-induced WDR5 degradation caused disassociation of the MLL/KMT2A complex off
chromatin, resulting in decreased H3K4me2. Transcriptomic profiling revealed that targets of both WDR5 and
IMiDs:CRBN were significantly repressed by treatment of MS40. In MLL-rearranged
leukemias, which exhibit IKZF1 high expression and dependency, co-suppression of WDR5 and Ikaros by MS40 is superior in suppressing
oncogenesis to the WDR5 PPI inhibitor, to MS40's non-
PROTAC analog controls (MS40N1 and MS40N2, which do not bind CRBN and WDR5, respectively), and to a matched VHL-based WDR5
PROTAC (MS169, which degrades WDR5 but not Ikaros). MS40 suppressed the growth of primary
leukemia patient cells in vitro and patient-derived xenografts in vivo. Thus, dual degradation of WDR5 and Ikaros is a promising anti-
cancer strategy.