Discovery of WDR5–MLL1 and HDAC Dual-Target Inhibitors for the Treatment of Acute Myeloid Leukemia

Targeting
the WDR5–MLL1 protein–protein interaction
(PPI) is considered to be an effective approach for the treatment
of MLL-rearranged leukemia. However, interfering with WDR5–MLL1
PPI reduces methylated H3K4 levels and induces a decline in acetylated
H3 levels, which may contribute to the suboptimal cellular efficacy
of WDR5 inhibitors. We observed that cotreatment with WDR5–MLL1
PPI and HDAC inhibitors augmented the antiproliferative effect in
MV-4-11 cells. Thus, a series of dual-target inhibitors was developed
by merging the pharmacophores of the WDR5 and HDAC inhibitors. Among
the developed inhibitors, compound 32d displayed an 89-fold
increase in antiproliferative efficacy and induced potent cell apoptosis
by impeding the DNA damage repair signaling pathway. Furthermore,
the administration of 30 mg/kg of compound 32d was well
tolerated, inhibiting MV-4-11 xenograft growth by 87.1%. Our investigation
established the therapeutic effectiveness of the developed WDR5–MLL1/HDAC
dual-target inhibitor against acute myeloid leukemia, providing a
valuable tool for further exploration of crosstalk between the two
targets.