Discovery of 5-(3-Chlorophenylamino)benzo[ c][2,6]naphthyridine Derivatives as Highly Selective CK2 Inhibitors with Potent Cancer Cell Stemness Inhibition

Yuanjiang Wang; Zhaodan Lv; Feihong Chen; Xing Wang; Shaohua Gou

doi:10.1021/acs.jmedchem.1c00131

Discovery of 5-(3-Chlorophenylamino)benzo[ c][2,6]naphthyridine Derivatives as Highly Selective CK2 Inhibitors with Potent Cancer Cell Stemness Inhibition

J Med Chem. 2021 Apr 22;64(8):5082-5098. doi: 10.1021/acs.jmedchem.1c00131. Epub 2021 Apr 9.

Authors

Yuanjiang Wang^{1

2}, Zhaodan Lv², Feihong Chen^{1

2}, Xing Wang², Shaohua Gou^{1

2}

Affiliations

¹ Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, PR China.
² Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China.

PMID: 33834781
DOI: 10.1021/acs.jmedchem.1c00131

Abstract

Multifunctional entities have recently been attractive for the development of anticancer chemotherapeutic drugs. However, such entities with concurrent CK2 along with cancer stem cell (CSC) inhibitory activities are rare in a single small molecule. Herein, a series of 5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine derivatives were synthesized using a known CK2 inhibitor, silmitasertib (CX-4945), as the lead compound. Among the resulting compounds, 1c exhibited stronger CK2 inhibitory activity with higher Clk2/CK2 selectivity than CX-4945. Significantly, 1c could modulate the Akt1(ser129)-GSK-3β(ser9)-Wnt/β-catenin signaling pathway and inhibit the expression of the stemness marker ALDH1A1, CSC surface antigens, and stem genes, showing potent CSC inhibitory activity. Moreover, 1c also displayed superior pharmacokinetics and antitumor activity compared with CX-4945 sodium salt, without obvious toxicity. The favorable antiproliferative and antitumor activity of 1c, its high inhibitory selectivity for CK2, and its potent inhibition of cancer cell stemness make this molecule a candidate for the treatment of cancer.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents / chemistry*
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Apoptosis / drug effects
Binding Sites
Casein Kinase II / antagonists & inhibitors*
Casein Kinase II / metabolism
Cell Cycle Checkpoints / drug effects
Drug Screening Assays, Antitumor
Humans
Mice
Mice, Nude
Molecular Docking Simulation
Naphthyridines / chemistry*
Naphthyridines / metabolism
Naphthyridines / pharmacology
Naphthyridines / therapeutic use
Neoplasms / drug therapy
Neoplasms / pathology
Neoplastic Stem Cells / cytology
Neoplastic Stem Cells / drug effects
Neoplastic Stem Cells / metabolism
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Protein Kinases / chemistry
Protein Kinases / metabolism
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Wnt Signaling Pathway / drug effects

Substances

Antineoplastic Agents
Naphthyridines
Protein Kinase Inhibitors
Protein Kinases
Casein Kinase II