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1.
J Adv Res ; 47: 173-187, 2023 05.
Article in English | MEDLINE | ID: mdl-35963541

ABSTRACT

INTRODUCTION: HER2 overexpression induces cancer aggression and frequent recurrences in many solid tumors. Because HER2 overproduction is generally followed by gene amplification, inhibition of protein-protein interaction (PPI) between transcriptional factor ELF3 and its coactivator MED23 has been considered an effective but challenging strategy. OBJECTIVES: This study aimed to determine the hotspot of ELF3-MED23 PPI and further specify the essential residues and their key interactions in the hotspot which are controllable by small molecules with significant anticancer activity. METHODS: Intensive biological evaluation methods including SEAP, fluorescence polarization, LC-MS/MS-based quantitative, biosensor, GST-pull down assays, and in silico structural analysis were performed to determine hotspot of ELF3-MED23 PPI and to elicit YK1, a novel small molecule PPI inhibitor. The effects of YK1 on possible PPIs of MED23 and the efficacy of trastuzumab were assessed using cell culture and tumor xenograft mouse models. RESULTS: ELF3-MED23 PPI was found to be specifically dependent on H-bondings between D400, H449 of MED23 and W138, I140 of ELF3 for upregulating HER2 gene transcription. Employing YK1, we confirmed that interruption on these H-bondings significantly attenuated the HER2-mediated oncogenic signaling cascades and exhibited significant in vitro and in vivo anticancer activity against HER2-overexpressing breast and gastric cancers even in their trastuzumab refractory clones. CONCLUSION: Our approach to develop specific ELF3-MED23 PPI inhibitor without interfering other PPIs of MED23 can finally lead to successful development of a drug resistance-free compound to interrogate HER2 biology in diverse conditions of cancers overexpressing HER2.


Subject(s)
Antineoplastic Agents , Neoplasms , Humans , Animals , Mice , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Receptor, ErbB-2/metabolism , Antibodies, Monoclonal, Humanized/pharmacology , Chromatography, Liquid , Hydrogen Bonding , Tandem Mass Spectrometry , Trastuzumab/pharmacology , DNA-Binding Proteins/genetics , Transcription Factors , Proto-Oncogene Proteins c-ets , Mediator Complex
2.
Bioorg Chem ; 111: 104884, 2021 06.
Article in English | MEDLINE | ID: mdl-33872925

ABSTRACT

The objective of this study was to discover potential topoisomerase (topo) targeting anticancer agents. Novel series of hydroxylated and halogenated(-F, -Cl, and -CF3) 2,4-diaryl benzofuro[3,2-b]pyridin-7-ols were systematically designed and synthesized by faster, economic, and environmentally friendly l-proline catalyzed and microwave-assisted one pot reaction method. The synthesized compounds were assessed for topo I and IIα inhibitory and anti-proliferative activities. The in vitroevaluation displayed that most of the compounds have selective topo IIα inhibitoryactivity as well as selectivity towards T47D human cancer cell line. Structure-activity relationship study suggested that the introduction of additional hydroxyl functionality at 7-positon of benzofuro[3,2-b]pyridine skeleton is crucial for selective topo IIα inhibitory activity. Placement of phenolic moiety on the 4-position of the tricyclic system imparts better topo IIα inhibitory and anti-proliferative activity.


Subject(s)
Antineoplastic Agents/pharmacology , Benzofurans/pharmacology , Poly-ADP-Ribose Binding Proteins/antagonists & inhibitors , Pyridines/pharmacology , Topoisomerase II Inhibitors/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzofurans/chemical synthesis , Benzofurans/chemistry , Cell Proliferation/drug effects , DNA Topoisomerases, Type II/metabolism , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Halogenation , Humans , Hydroxylation , Molecular Structure , Poly-ADP-Ribose Binding Proteins/metabolism , Pyridines/chemical synthesis , Pyridines/chemistry , Structure-Activity Relationship , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/chemistry , Tumor Cells, Cultured
3.
Bioorg Chem ; 84: 347-354, 2019 03.
Article in English | MEDLINE | ID: mdl-30530076

ABSTRACT

Human DNA topoisomerases (topos) have been recognized as a good target molecule for the development of anticancer drugs because they play an important role in solving DNA topological problems caused by DNA strand separation during replication and transcription. In this study, we designed and synthesized 11 novel chromone backbone compounds possessing epoxy and halohydrin substituents with chirality. In the topos inhibition test, compounds 2, 9, 10, and 11 showed comparable topo I inhibitory activity at concentration of 100 µM compared to camptothecin, and all of the synthesized compounds showed moderate topo IIα inhibitory activity. Among them, compounds 9, 10 and 11 were more potent than the others in both topo I and IIα inhibitory activity. Compound 11 showed the most potent cell antiproliferative activity against all tested cancer cell lines with particularly strong inhibition (an IC50 of 0.04 µM) of K562 myelogenous leukemia cancer cell proliferation. In the brief structure-activity relationship analysis, there was no clear correlation between stereochemistry and topos inhibitory and cytotoxic activity. 5(R),7(S)-bisepoxy-substituted compound 11 was the most potent DNA cross-linker and induced G2/M arrest in a cell cycle assay in a dose- and time-dependent manner. After the treatment time period induced apoptosis in K562 cells without increasing G2/M-phase cells. Overall, compound 11 showed good consistent inhibitory biological activity related to cancer cell proliferation.


Subject(s)
Antineoplastic Agents/chemical synthesis , Chromones/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Chromones/pharmacology , DNA Topoisomerases, Type I/chemistry , DNA Topoisomerases, Type I/metabolism , DNA Topoisomerases, Type II/chemistry , DNA Topoisomerases, Type II/metabolism , G2 Phase Cell Cycle Checkpoints/drug effects , Humans , M Phase Cell Cycle Checkpoints/drug effects , Stereoisomerism , Structure-Activity Relationship , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/metabolism , Topoisomerase II Inhibitors/pharmacology
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