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

Hacer Karatas; Yangbing Li; Liu Liu; Jiao Ji; Shirley Lee; Yong Chen; Jiuling Yang; Liyue Huang; Denzil Bernard; Jing Xu; Elizabeth C Townsend; Fang Cao; Xu Ran; Xiaoqin Li; Bo Wen; Duxin Sun; Jeanne A Stuckey; Ming Lei; Yali Dou; Shaomeng Wang

doi:10.1021/acs.jmedchem.6b01796

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. Epub 2017 Jun 12.

Authors

Hacer Karatas¹, Yangbing Li¹, Liu Liu¹, Jiao Ji¹, Shirley Lee¹, Yong Chen¹, Jiuling Yang¹, Liyue Huang¹, Denzil Bernard¹, Jing Xu¹, Elizabeth C Townsend¹, Fang Cao¹, Xu Ran¹, Xiaoqin Li¹, Bo Wen¹, Duxin Sun¹, Jeanne A Stuckey¹, Ming Lei¹, Yali Dou¹, Shaomeng Wang¹

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 (K_i 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.

MeSH terms

Animals
Binding, Competitive
Cell Line, Tumor
Cell Survival / drug effects
Chemistry Techniques, Synthetic
Drug Discovery
Drug Stability
High-Throughput Screening Assays / methods
Histone-Lysine N-Methyltransferase / chemistry
Histone-Lysine N-Methyltransferase / genetics
Histone-Lysine N-Methyltransferase / metabolism*
Humans
Intracellular Signaling Peptides and Proteins
Leukemia / drug therapy
Leukemia / pathology
Macrocyclic Compounds / chemical synthesis
Macrocyclic Compounds / chemistry
Macrocyclic Compounds / pharmacology
Magnetic Resonance Spectroscopy
Mice
Microsomes / drug effects
Molecular Docking Simulation
Myeloid-Lymphoid Leukemia Protein / genetics
Myeloid-Lymphoid Leukemia Protein / metabolism*
Peptides, Cyclic / chemistry
Peptides, Cyclic / pharmacology*
Peptidomimetics / chemistry*
Peptidomimetics / metabolism
Peptidomimetics / pharmacology*
Protein Interaction Domains and Motifs
Rats

Substances

Intracellular Signaling Peptides and Proteins
KMT2A protein, human
MM-589
Macrocyclic Compounds
Peptides, Cyclic
Peptidomimetics
WDR5 protein, human
Myeloid-Lymphoid Leukemia Protein
Histone-Lysine N-Methyltransferase

Grants and funding

R01 CA177307/CA/NCI NIH HHS/United States