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Thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione Derivative Inhibits d-Dopachrome Tautomerase Activity and Suppresses the Proliferation of Non-Small Cell Lung Cancer Cells
[Image: see text] The homologous cytokines macrophage migration inhibitory factor (MIF) and d-dopachrome tautomerase (d-DT or MIF2) play key roles in cancers. Molecules binding to the MIF tautomerase active site interfere with its biological activity. In contrast, the lack of potent MIF2 inhibitors...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8842245/ https://www.ncbi.nlm.nih.gov/pubmed/35041425 http://dx.doi.org/10.1021/acs.jmedchem.1c01598 |
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author | Xiao, Zhangping Osipyan, Angelina Song, Shanshan Chen, Deng Schut, Reinder A. van Merkerk, Ronald van der Wouden, Petra E. Cool, Robbert H. Quax, Wim J. Melgert, Barbro N. Poelarends, Gerrit J. Dekker, Frank J. |
author_facet | Xiao, Zhangping Osipyan, Angelina Song, Shanshan Chen, Deng Schut, Reinder A. van Merkerk, Ronald van der Wouden, Petra E. Cool, Robbert H. Quax, Wim J. Melgert, Barbro N. Poelarends, Gerrit J. Dekker, Frank J. |
author_sort | Xiao, Zhangping |
collection | PubMed |
description | [Image: see text] The homologous cytokines macrophage migration inhibitory factor (MIF) and d-dopachrome tautomerase (d-DT or MIF2) play key roles in cancers. Molecules binding to the MIF tautomerase active site interfere with its biological activity. In contrast, the lack of potent MIF2 inhibitors hinders the exploration of MIF2 as a drug target. In this work, screening of a focused compound collection enabled the identification of a MIF2 tautomerase inhibitor R110. Subsequent optimization provided inhibitor 5d with an IC(50) of 1.0 μM for MIF2 tautomerase activity and a high selectivity over MIF. 5d suppressed the proliferation of non-small cell lung cancer cells in two-dimensional (2D) and three-dimensional (3D) cell cultures, which can be explained by the induction of cell cycle arrest via deactivation of the mitogen-activated protein kinase (MAPK) pathway. Thus, we discovered and characterized MIF2 inhibitors (5d) with improved antiproliferative activity in cellular models systems, which indicates the potential of targeting MIF2 in cancer treatment. |
format | Online Article Text |
id | pubmed-8842245 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-88422452022-02-15 Thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione Derivative Inhibits d-Dopachrome Tautomerase Activity and Suppresses the Proliferation of Non-Small Cell Lung Cancer Cells Xiao, Zhangping Osipyan, Angelina Song, Shanshan Chen, Deng Schut, Reinder A. van Merkerk, Ronald van der Wouden, Petra E. Cool, Robbert H. Quax, Wim J. Melgert, Barbro N. Poelarends, Gerrit J. Dekker, Frank J. J Med Chem [Image: see text] The homologous cytokines macrophage migration inhibitory factor (MIF) and d-dopachrome tautomerase (d-DT or MIF2) play key roles in cancers. Molecules binding to the MIF tautomerase active site interfere with its biological activity. In contrast, the lack of potent MIF2 inhibitors hinders the exploration of MIF2 as a drug target. In this work, screening of a focused compound collection enabled the identification of a MIF2 tautomerase inhibitor R110. Subsequent optimization provided inhibitor 5d with an IC(50) of 1.0 μM for MIF2 tautomerase activity and a high selectivity over MIF. 5d suppressed the proliferation of non-small cell lung cancer cells in two-dimensional (2D) and three-dimensional (3D) cell cultures, which can be explained by the induction of cell cycle arrest via deactivation of the mitogen-activated protein kinase (MAPK) pathway. Thus, we discovered and characterized MIF2 inhibitors (5d) with improved antiproliferative activity in cellular models systems, which indicates the potential of targeting MIF2 in cancer treatment. American Chemical Society 2022-01-18 2022-02-10 /pmc/articles/PMC8842245/ /pubmed/35041425 http://dx.doi.org/10.1021/acs.jmedchem.1c01598 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Xiao, Zhangping Osipyan, Angelina Song, Shanshan Chen, Deng Schut, Reinder A. van Merkerk, Ronald van der Wouden, Petra E. Cool, Robbert H. Quax, Wim J. Melgert, Barbro N. Poelarends, Gerrit J. Dekker, Frank J. Thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione Derivative Inhibits d-Dopachrome Tautomerase Activity and Suppresses the Proliferation of Non-Small Cell Lung Cancer Cells |
title | Thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione Derivative Inhibits d-Dopachrome Tautomerase
Activity and Suppresses the
Proliferation of Non-Small Cell Lung Cancer Cells |
title_full | Thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione Derivative Inhibits d-Dopachrome Tautomerase
Activity and Suppresses the
Proliferation of Non-Small Cell Lung Cancer Cells |
title_fullStr | Thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione Derivative Inhibits d-Dopachrome Tautomerase
Activity and Suppresses the
Proliferation of Non-Small Cell Lung Cancer Cells |
title_full_unstemmed | Thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione Derivative Inhibits d-Dopachrome Tautomerase
Activity and Suppresses the
Proliferation of Non-Small Cell Lung Cancer Cells |
title_short | Thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione Derivative Inhibits d-Dopachrome Tautomerase
Activity and Suppresses the
Proliferation of Non-Small Cell Lung Cancer Cells |
title_sort | thieno[2,3-d]pyrimidine-2,4(1h,3h)-dione derivative inhibits d-dopachrome tautomerase
activity and suppresses the
proliferation of non-small cell lung cancer cells |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8842245/ https://www.ncbi.nlm.nih.gov/pubmed/35041425 http://dx.doi.org/10.1021/acs.jmedchem.1c01598 |
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