Suppression of Drug-Resistant Non-Small-Cell Lung Cancer with Inhibitors Targeting Minichromosomal Maintenance Protein

Chia-Yi Lin; Hsin-Yi Wu; Yuan-Ling Hsu; Ting-Jen Rachel Cheng; Jyung-Hurng Liu; Rou-Jie Huang; Tzu-Hung Hsiao; Chia-Jen Wang; Pei-Fang Hung; Albert Lan; Szu-Hua Pan; Rong-Jie Chein; Chi-Huey Wong; Pan-Chyr Yang

doi:10.1021/acs.jmedchem.9b01783

Suppression of Drug-Resistant Non-Small-Cell Lung Cancer with Inhibitors Targeting Minichromosomal Maintenance Protein

J Med Chem. 2020 Mar 26;63(6):3172-3187. doi: 10.1021/acs.jmedchem.9b01783. Epub 2020 Mar 17.

Authors

Chia-Yi Lin^{1

2}, Hsin-Yi Wu³, Yuan-Ling Hsu⁴, Ting-Jen Rachel Cheng⁵, Jyung-Hurng Liu^{6

7

8}, Rou-Jie Huang⁹, Tzu-Hung Hsiao¹⁰, Chia-Jen Wang¹¹, Pei-Fang Hung², Albert Lan⁴, Szu-Hua Pan^{1

4

12}, Rong-Jie Chein³, Chi-Huey Wong⁵, Pan-Chyr Yang^{1

2

13}

Affiliations

¹ Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei 100, Taiwan.
² Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
³ Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan.
⁴ Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
⁵ The Genomics Research Center, Academia Sinica, Taipei 115, Taiwan.
⁶ Institute of Genomics and Bioinformatics, College of Life Sciences, National Chung Hsing University, Taichung 402, Taiwan.
⁷ Agricultural Biotechnology Center, NCHU, Taichung 402, Taiwan.
⁸ Rong Hsing Research Center for Translational Medicine, NCHU, Taichung 402, Taiwan.
⁹ Department of Chemistry, National Central University, Jhong-Li 320, Taiwan.
¹⁰ Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan.
¹¹ Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan.
¹² Doctoral Degree Program of Translational Medicine, National Taiwan University, Taipei 100, Taiwan.
¹³ Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan.

PMID: 32125853
DOI: 10.1021/acs.jmedchem.9b01783

Abstract

Drug resistance has been a major threat in cancer therapies that necessitates the development of new strategies to overcome this problem. We report here a cell-based high-throughput screen of a library containing two-million molecules for the compounds that inhibit the proliferation of non-small-cell lung cancer (NSCLC). Through the process of phenotypic screening, target deconvolution, and structure-activity relationship (SAR) analysis, a compound of furanonaphthoquinone-based small molecule, AS4583, was identified that exhibited potent activity in tyrosine kinase inhibitor (TKI)-sensitive and TKI-resistant NSCLC cells (IC₅₀ = 77 nM) and in xenograft mice. The mechanistic studies revealed that AS4583 inhibited cell-cycle progression and reduced DNA replication by disrupting the formation of the minichromosomal maintenance protein (MCM) complex. Subsequent SAR study of AS4583 gave compound RJ-LC-07-48 which exhibited greater potency in drug-resistant NSCLC cells (IC₅₀ = 17 nM) and in mice with H1975 xenograft tumor.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / metabolism
Antineoplastic Agents / therapeutic use*
Binding Sites
Carcinoma, Non-Small-Cell Lung / drug therapy*
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Resistance, Neoplasm / drug effects
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / therapeutic use
Furans / chemical synthesis
Furans / metabolism
Furans / therapeutic use*
High-Throughput Screening Assays
Humans
Lung Neoplasms / drug therapy*
Mice, Nude
Minichromosome Maintenance Proteins / metabolism*
Molecular Docking Simulation
Molecular Structure
Naphthoquinones / chemical synthesis
Naphthoquinones / metabolism
Naphthoquinones / therapeutic use*
Protein Binding
Small Molecule Libraries / pharmacology
Structure-Activity Relationship
Ubiquitination / drug effects
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Enzyme Inhibitors
Furans
Naphthoquinones
Small Molecule Libraries
Minichromosome Maintenance Proteins