Novel structured ADAM17 small-molecule inhibitor represses ADAM17/Notch pathway activation and the NSCLC cells’ resistance to anti-tumour drugs
Background and aims: The outcomes of current treatment for non-small cell lung cancer (NSCLC) are unsatisfactory and development of new and more efficacious therapeutic strategies are required. The Notch pathway, which is necessary for cell survival to avert apoptosis, induces the resistance of canc...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-06-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1189245/full |
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| author | Meng Chi Yamin Jie Ying Li Ying Li Duo Wang Man Li Dan Li Mingyan E Yongwu Li Na Liu Anxin Gu Guanghua Rong |
| author_facet | Meng Chi Yamin Jie Ying Li Ying Li Duo Wang Man Li Dan Li Mingyan E Yongwu Li Na Liu Anxin Gu Guanghua Rong |
| author_sort | Meng Chi |
| collection | DOAJ |
| description | Background and aims: The outcomes of current treatment for non-small cell lung cancer (NSCLC) are unsatisfactory and development of new and more efficacious therapeutic strategies are required. The Notch pathway, which is necessary for cell survival to avert apoptosis, induces the resistance of cancer cells to antitumour drugs. Notch pathway activation is controlled by the cleavage of Notch proteins/receptors mediated by A disintegrin and metalloproteinase 17 (ADAM17); therefore, ADAM17 is a reliable intervention target for anti-tumour therapy to overcome the drug resistance of cancer cells. This work aims to develop and elucidate the activation of Compound 2b, a novel-structured small-molecule inhibitor of ADAM17, which was designed and developed and its therapeutic efficacy in NSCLC was assessed via multi-assays.Methods and results: A lead compound for a potential inhibitor of ADAM17 was explored via pharmacophore modelling, molecular docking, and biochemical screening. It was augmented by substituting two important chemical groups [R1 and R2 of the quinoxaline-2,3-diamine (its chemical skeleton)]; subsequently, serial homologs of the lead compound were used to obtain anoptimized compound (2b) with high inhibitory activity compared with leading compound against ADAM17 to inhibit the cleavage of Notch proteins and the accumulation of the Notch intracellular domain in the nuclei of NSCLC cells. The inhibitory activity of compound 2b was demonstrated by quantitative polymerase chain reaction and Western blotting. The specificity of compound 2b on ADAM17 was confirmed via point-mutation. Compound 2b enhanced the activation of antitumor drugs on NSCLC cells, in cell lines and nude mice models, by targeting the ADAM17/Notch pathway.Conclusion: Compound 2b may be a promising strategy for NSCLC treatment. |
| first_indexed | 2024-03-13T02:34:59Z |
| format | Article |
| id | doaj.art-1ec00fe69a244e06959769bb2c55fd76 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-13T02:34:59Z |
| publishDate | 2023-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-1ec00fe69a244e06959769bb2c55fd762023-06-29T05:42:56ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-06-011410.3389/fphar.2023.11892451189245Novel structured ADAM17 small-molecule inhibitor represses ADAM17/Notch pathway activation and the NSCLC cells’ resistance to anti-tumour drugsMeng Chi0Yamin Jie1Ying Li2Ying Li3Duo Wang4Man Li5Dan Li6Mingyan E7Yongwu Li8Na Liu9Anxin Gu10Guanghua Rong11Department of Anesthesiology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, ChinaDepartment of Radiation Oncology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, ChinaHeilongjiang Provincial Key Laboratory of Hard Tissue Development and Regeneration, The Second Affiliated Hospital of Harbin Medical University, Harbin, ChinaHeilongjiang Academy of Medical Sciences, Harbin, ChinaDepartment of Neurology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, ChinaDepartment of Endoscopy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, ChinaDepartment of Radiation Oncology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, ChinaDepartment of Radiation Oncology, Harbin Medical University Cancer Hospital, Heilongjiang, ChinaDepartment of Nuclear Medicine, The Fifth Medical Center of PLA General Hospital, Beijing, ChinaDepartment of Nuclear Medicine, The Fifth Medical Center of PLA General Hospital, Beijing, ChinaDepartment of Radiation Oncology, Harbin Medical University Cancer Hospital, Heilongjiang, ChinaDepartment of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, ChinaBackground and aims: The outcomes of current treatment for non-small cell lung cancer (NSCLC) are unsatisfactory and development of new and more efficacious therapeutic strategies are required. The Notch pathway, which is necessary for cell survival to avert apoptosis, induces the resistance of cancer cells to antitumour drugs. Notch pathway activation is controlled by the cleavage of Notch proteins/receptors mediated by A disintegrin and metalloproteinase 17 (ADAM17); therefore, ADAM17 is a reliable intervention target for anti-tumour therapy to overcome the drug resistance of cancer cells. This work aims to develop and elucidate the activation of Compound 2b, a novel-structured small-molecule inhibitor of ADAM17, which was designed and developed and its therapeutic efficacy in NSCLC was assessed via multi-assays.Methods and results: A lead compound for a potential inhibitor of ADAM17 was explored via pharmacophore modelling, molecular docking, and biochemical screening. It was augmented by substituting two important chemical groups [R1 and R2 of the quinoxaline-2,3-diamine (its chemical skeleton)]; subsequently, serial homologs of the lead compound were used to obtain anoptimized compound (2b) with high inhibitory activity compared with leading compound against ADAM17 to inhibit the cleavage of Notch proteins and the accumulation of the Notch intracellular domain in the nuclei of NSCLC cells. The inhibitory activity of compound 2b was demonstrated by quantitative polymerase chain reaction and Western blotting. The specificity of compound 2b on ADAM17 was confirmed via point-mutation. Compound 2b enhanced the activation of antitumor drugs on NSCLC cells, in cell lines and nude mice models, by targeting the ADAM17/Notch pathway.Conclusion: Compound 2b may be a promising strategy for NSCLC treatment.https://www.frontiersin.org/articles/10.3389/fphar.2023.1189245/fullnon-small-cell lung cancerantitumour drugssmall-molecule inhibitorlung adenocarcinomalung squamous cell carcinoma |
| spellingShingle | Meng Chi Yamin Jie Ying Li Ying Li Duo Wang Man Li Dan Li Mingyan E Yongwu Li Na Liu Anxin Gu Guanghua Rong Novel structured ADAM17 small-molecule inhibitor represses ADAM17/Notch pathway activation and the NSCLC cells’ resistance to anti-tumour drugs Frontiers in Pharmacology non-small-cell lung cancer antitumour drugs small-molecule inhibitor lung adenocarcinoma lung squamous cell carcinoma |
| title | Novel structured ADAM17 small-molecule inhibitor represses ADAM17/Notch pathway activation and the NSCLC cells’ resistance to anti-tumour drugs |
| title_full | Novel structured ADAM17 small-molecule inhibitor represses ADAM17/Notch pathway activation and the NSCLC cells’ resistance to anti-tumour drugs |
| title_fullStr | Novel structured ADAM17 small-molecule inhibitor represses ADAM17/Notch pathway activation and the NSCLC cells’ resistance to anti-tumour drugs |
| title_full_unstemmed | Novel structured ADAM17 small-molecule inhibitor represses ADAM17/Notch pathway activation and the NSCLC cells’ resistance to anti-tumour drugs |
| title_short | Novel structured ADAM17 small-molecule inhibitor represses ADAM17/Notch pathway activation and the NSCLC cells’ resistance to anti-tumour drugs |
| title_sort | novel structured adam17 small molecule inhibitor represses adam17 notch pathway activation and the nsclc cells resistance to anti tumour drugs |
| topic | non-small-cell lung cancer antitumour drugs small-molecule inhibitor lung adenocarcinoma lung squamous cell carcinoma |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1189245/full |
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