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Discovery of novel exceptionally potent and orally active c-MET PROTACs for the treatment of tumors with MET alterations
Various c-mesenchymal-to-epithelial transition (c-MET) inhibitors are effective in the treatment of non-small cell lung cancer; however, the inevitable drug resistance remains a challenge, limiting their clinical efficacy. Therefore, novel strategies targeting c-MET are urgently required. Herein, th...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10326257/ https://www.ncbi.nlm.nih.gov/pubmed/37425039 http://dx.doi.org/10.1016/j.apsb.2023.01.014 |
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author | Li, Pengyun Jia, Changkai Fan, Zhiya Hu, Xiaotong Zhang, Wenjuan Liu, Ke Sun, Shiyang Guo, Haoxin Yang, Ning Zhu, Maoxiang Zhuang, Xiaomei Xiao, Junhai Zheng, Zhibing Li, Song |
author_facet | Li, Pengyun Jia, Changkai Fan, Zhiya Hu, Xiaotong Zhang, Wenjuan Liu, Ke Sun, Shiyang Guo, Haoxin Yang, Ning Zhu, Maoxiang Zhuang, Xiaomei Xiao, Junhai Zheng, Zhibing Li, Song |
author_sort | Li, Pengyun |
collection | PubMed |
description | Various c-mesenchymal-to-epithelial transition (c-MET) inhibitors are effective in the treatment of non-small cell lung cancer; however, the inevitable drug resistance remains a challenge, limiting their clinical efficacy. Therefore, novel strategies targeting c-MET are urgently required. Herein, through rational structure optimization, we obtained novel exceptionally potent and orally active c-MET proteolysis targeting chimeras (PROTACs) namely D10 and D15 based on thalidomide and tepotinib. D10 and D15 inhibited cell growth with low nanomolar IC(50) values and achieved picomolar DC(50) values and >99% of maximum degradation (D(max)) in EBC-1 and Hs746T cells. Mechanistically, D10 and D15 dramatically induced cell apoptosis, G1 cell cycle arrest and inhibited cell migration and invasion. Notably, intraperitoneal administration of D10 and D15 significantly inhibited tumor growth in the EBC-1 xenograft model and oral administration of D15 induced approximately complete tumor suppression in the Hs746T xenograft model with well-tolerated dose-schedules. Furthermore, D10 and D15 exerted significant anti-tumor effect in cells with c-MET(Y1230H) and c-MET(D1228N) mutations, which are resistant to tepotinib in clinic. These findings demonstrated that D10 and D15 could serve as candidates for the treatment of tumors with MET alterations. |
format | Online Article Text |
id | pubmed-10326257 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-103262572023-07-08 Discovery of novel exceptionally potent and orally active c-MET PROTACs for the treatment of tumors with MET alterations Li, Pengyun Jia, Changkai Fan, Zhiya Hu, Xiaotong Zhang, Wenjuan Liu, Ke Sun, Shiyang Guo, Haoxin Yang, Ning Zhu, Maoxiang Zhuang, Xiaomei Xiao, Junhai Zheng, Zhibing Li, Song Acta Pharm Sin B Original Article Various c-mesenchymal-to-epithelial transition (c-MET) inhibitors are effective in the treatment of non-small cell lung cancer; however, the inevitable drug resistance remains a challenge, limiting their clinical efficacy. Therefore, novel strategies targeting c-MET are urgently required. Herein, through rational structure optimization, we obtained novel exceptionally potent and orally active c-MET proteolysis targeting chimeras (PROTACs) namely D10 and D15 based on thalidomide and tepotinib. D10 and D15 inhibited cell growth with low nanomolar IC(50) values and achieved picomolar DC(50) values and >99% of maximum degradation (D(max)) in EBC-1 and Hs746T cells. Mechanistically, D10 and D15 dramatically induced cell apoptosis, G1 cell cycle arrest and inhibited cell migration and invasion. Notably, intraperitoneal administration of D10 and D15 significantly inhibited tumor growth in the EBC-1 xenograft model and oral administration of D15 induced approximately complete tumor suppression in the Hs746T xenograft model with well-tolerated dose-schedules. Furthermore, D10 and D15 exerted significant anti-tumor effect in cells with c-MET(Y1230H) and c-MET(D1228N) mutations, which are resistant to tepotinib in clinic. These findings demonstrated that D10 and D15 could serve as candidates for the treatment of tumors with MET alterations. Elsevier 2023-06 2023-01-19 /pmc/articles/PMC10326257/ /pubmed/37425039 http://dx.doi.org/10.1016/j.apsb.2023.01.014 Text en © 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Li, Pengyun Jia, Changkai Fan, Zhiya Hu, Xiaotong Zhang, Wenjuan Liu, Ke Sun, Shiyang Guo, Haoxin Yang, Ning Zhu, Maoxiang Zhuang, Xiaomei Xiao, Junhai Zheng, Zhibing Li, Song Discovery of novel exceptionally potent and orally active c-MET PROTACs for the treatment of tumors with MET alterations |
title | Discovery of novel exceptionally potent and orally active c-MET PROTACs for the treatment of tumors with MET alterations |
title_full | Discovery of novel exceptionally potent and orally active c-MET PROTACs for the treatment of tumors with MET alterations |
title_fullStr | Discovery of novel exceptionally potent and orally active c-MET PROTACs for the treatment of tumors with MET alterations |
title_full_unstemmed | Discovery of novel exceptionally potent and orally active c-MET PROTACs for the treatment of tumors with MET alterations |
title_short | Discovery of novel exceptionally potent and orally active c-MET PROTACs for the treatment of tumors with MET alterations |
title_sort | discovery of novel exceptionally potent and orally active c-met protacs for the treatment of tumors with met alterations |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10326257/ https://www.ncbi.nlm.nih.gov/pubmed/37425039 http://dx.doi.org/10.1016/j.apsb.2023.01.014 |
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