Discovery of DDO-2213 as a Potent and Orally Bioavailable Inhibitor of the WDR5-Mixed Lineage Leukemia 1 Protein-Protein Interaction for the Treatment of MLL Fusion Leukemia

Weilin Chen; Xin Chen; Dongdong Li; Jianrui Zhou; Zhengyu Jiang; Qidong You; Xiaoke Guo

doi:10.1021/acs.jmedchem.1c00091

Discovery of DDO-2213 as a Potent and Orally Bioavailable Inhibitor of the WDR5-Mixed Lineage Leukemia 1 Protein-Protein Interaction for the Treatment of MLL Fusion Leukemia

J Med Chem. 2021 Jun 24;64(12):8221-8245. doi: 10.1021/acs.jmedchem.1c00091. Epub 2021 Jun 9.

Authors

Weilin Chen^{1

2}, Xin Chen¹, Dongdong Li¹, Jianrui Zhou¹, Zhengyu Jiang^{1

3}, Qidong You^{1

3}, Xiaoke Guo^{1

3}

Affiliations

¹ Jiangsu Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
² Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
³ Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.

PMID: 34105966
DOI: 10.1021/acs.jmedchem.1c00091

Abstract

WD repeat-containing protein 5 (WDR5) is essential for the stability and methyltransferase activity of the mixed lineage leukemia 1 (MLL1) complex. Dysregulation of the MLL1 gene is associated with human acute leukemias, and the direct disruption of the WDR5-MLL1 protein-protein interaction (PPI) is emerging as an alternative strategy for MLL-rearranged cancers. Here, we represent a new aniline pyrimidine scaffold for WDR5-MLL1 inhibitors. A comprehensive structure-activity analysis identified a potent inhibitor 63 (DDO-2213), with an IC₅₀ of 29 nM in a competitive fluorescence polarization assay and a K_d value of 72.9 nM for the WDR5 protein. Compound 63 selectively inhibited MLL histone methyltransferase activity and the proliferation of MLL translocation-harboring cells. Furthermore, 63 displayed good pharmacokinetic properties and suppressed the growth of MV4-11 xenograft tumors in mice after oral administration, first verifying the in vivo efficacy of targeting the WDR5-MLL1 PPI by small molecules.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aniline Compounds / chemical synthesis
Aniline Compounds / metabolism
Aniline Compounds / pharmacokinetics
Aniline Compounds / therapeutic use
Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / therapeutic use*
Cell Proliferation / drug effects
Drug Stability
Female
Histone-Lysine N-Methyltransferase / antagonists & inhibitors*
Histone-Lysine N-Methyltransferase / metabolism
Humans
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
Intracellular Signaling Peptides and Proteins / metabolism
Leukemia / drug therapy*
Male
Mice
Mice, Inbred BALB C
Microsomes, Liver / metabolism
Molecular Docking Simulation
Molecular Structure
Myeloid-Lymphoid Leukemia Protein / antagonists & inhibitors*
Myeloid-Lymphoid Leukemia Protein / metabolism
Protein Binding / drug effects*
Pyrimidines / chemical synthesis
Pyrimidines / metabolism
Pyrimidines / pharmacokinetics
Pyrimidines / therapeutic use
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Xenograft Model Antitumor Assays

Substances

Aniline Compounds
Antineoplastic Agents
Intracellular Signaling Peptides and Proteins
Pyrimidines
Wdr5 protein, mouse
Myeloid-Lymphoid Leukemia Protein
Histone-Lysine N-Methyltransferase
Kmt2a protein, mouse