Suppression of Drug-Resistant Non-Small-Cell Lung Cancer with Inhibitors Targeting Minichromosomal Maintenance Protein
Journal
Journal of Medicinal Chemistry
Journal Volume
63
Journal Issue
6
Pages
3172-3187
Date Issued
2020
Author(s)
Lin C.-Y.
Wu H.-Y.
Hsu Y.-L.
Cheng T.-J.R.
Liu J.-H.
Huang R.-J.
Hsiao T.-H.
Wang C.-J.
Hung P.-F.
Lan A.
Chein R.-J.
Wong C.-H.
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. ? 2020 American Chemical Society.
SDGs
Other Subjects
antineoplastic agent; as 4583; caspase 3; furanone derivative; minichromosome maintenance protein; minichromosome maintenance protein 2; n [3 (1h imidazol 1 yl)propyl] 2 methyl 4,9 dioxo 4,9 dihydronaphtho[2,3 b]furan 3 carboxamide; n [3 (1h imidazol 1 yl)propyl] 7 fluoro 2 methyl 4,9 dioxo 4,9 dihydronaphtho[2,3 b]furan 3 carboxamide; naphthalene derivative; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 1; protein inhibitor; protein tyrosine kinase inhibitor; quinone derivative; rj lc 07 48; short hairpin RNA; unclassified drug; antineoplastic agent; enzyme inhibitor; furan derivative; minichromosome maintenance protein; naphthoquinone; protein binding; amino terminal sequence; animal experiment; animal model; antineoplastic activity; antiproliferative activity; apoptosis; Article; cancer resistance; cancer size; cell cycle arrest; cell cycle M phase; cell cycle progression; cell cycle S phase; cell survival; cell synchronization; cell viability; chemosensitivity; clinical outcome; controlled study; DNA replication; drug cytotoxicity; drug efficacy; drug potency; HBEC cell line (bronchial epithelium); high throughput screening; human; human cell; IC50; in vivo study; lung non-small cell carcinoma cell line; male; mouse; non small cell lung cancer; nonhuman; overall survival; protein expression; structure activity relation; Sulfolobus solfataricus; tumor growth inhibition rate; tumor xenograft; animal; binding site; cell proliferation; chemical structure; drug effect; drug resistance; drug screening; lung tumor; metabolism; molecular docking; molecular library; non small cell lung cancer; nude mouse; pharmacology; synthesis; tumor cell line; ubiquitination; Animals; Antineoplastic Agents; Binding Sites; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Enzyme Inhibitors; Furans; High-Throughput Screening Assays; Humans; Lung Neoplasms; Mice, Nude; Minichromosome Maintenance Proteins; Molecular Docking Simulation; Molecular Structure; Naphthoquinones; Protein Binding; Small Molecule Libraries; Structure-Activity Relationship; Ubiquitination; Xenograft Model Antitumor Assays
Publisher
American Chemical Society
Type
journal article