2. Academic Validation
  3. 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

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

  • J Med Chem. 2017 Jun 22;60(12):4818-4839. doi: 10.1021/acs.jmedchem.6b01796.
Hacer Karatas 1,  Yangbing Li 1,  Liu Liu 1,  Jiao Ji 1,  Shirley Lee 1,  Yong Chen 1,  Jiuling Yang 1,  Liyue Huang 1,  Denzil Bernard 1,  Jing Xu 1,  Elizabeth C Townsend 1,  Fang Cao 1,  Xu Ran 1,  Xiaoqin Li 1,  Bo Wen 1,  Duxin Sun 1,  Jeanne A Stuckey 1,  Ming Lei 1,  Yali Dou 1,  Shaomeng Wang 1
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, ‡Department of Internal Medicine, §Comprehensive Cancer Center, ∥Department of Pathology, ⊥Howard Hughes Medical Institute, #Department of Biological Chemistry, ∇Department of Pharmaceutical Sciences, ○Department of Pharmacology, and ¶Life Sciences Institute, University of Michigan , Ann Arbor, Michigan 48109, United States.
PMID: 28603984 DOI: 10.1021/acs.jmedchem.6b01796
Abstract

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.

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