Discovery of a Highly Potent, Cell-Permeable Macrocyclic Peptidomimetic (MM-589) Targeting the WD Repeat Domain 5 Protein (WDR5)–Mixed Lineage Leukemia (MLL) Protein–Protein Interaction

We report herein
the design, synthesis, and evaluation of macrocyclic
peptidomimetics that bind to WD repeat domain 5 (WDR5) and block the
WDR5–mixed lineage leukemia (MLL) protein–protein interaction.
Compound 18 (MM-589) binds to WDR5 with an IC50 value of 0.90 nM (Ki value <1 nM)
and inhibits the MLL H3K4 methyltransferase (HMT) activity with an
IC50 value of 12.7 nM. Compound 18 potently
and selectively inhibits cell growth in human leukemia cell lines
harboring MLL translocations and is >40 times better than the previously
reported compound MM-401. Cocrystal structures of 16 and 18 complexed with WDR5 provide structural basis for their
high affinity binding to WDR5. Additionally, we have developed and
optimized a new AlphaLISA-based MLL HMT functional assay to facilitate
the functional evaluation of these designed compounds. Compound 18 represents the most potent inhibitor of the WDR5–MLL
interaction reported to date, and further optimization of 18 may yield a new therapy for acute leukemia.