Modification and Biological Evaluation of a Series of 1,5-Diaryl-1,2,4-triazole Compounds as Novel Agents against Pancreatic Cancer Metastasis through Targeting Myoferlin
Pancreatic cancer is one of the most common cancers with an extremely low survival rate. Metastasis, as one of the key reasons of cancer-related death, is found in more than 50% pancreatic cancer patients at diagnosis. Novel therapeutic targets and drugs blocking cancer metastasis are urgently neede...
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| Published in | Journal of medicinal chemistry Vol. 62; no. 10; pp. 4949 - 4966 |
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| Main Authors | , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
WASHINGTON
American Chemical Society
23.05.2019
Amer Chemical Soc |
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| Online Access | Get full text |
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| Abstract | Pancreatic cancer is one of the most common cancers with an extremely low survival rate. Metastasis, as one of the key reasons of cancer-related death, is found in more than 50% pancreatic cancer patients at diagnosis. Novel therapeutic targets and drugs blocking cancer metastasis are urgently needed. Herein, we report a series of 1,5-diaryl-1,2,4-triazole derivatives as potent antimetastatic agents. Lead compound 6y displayed effective antimetastatic activities in pancreatic cancer in vitro and in vivo. Concomitant studies indicated that 6y probably binds with myoferlin (MYOF), a novel potential antitumor metastasis target, which regulates vesicle trafficking and metastasis-related proteins. Subsequent biophysical and biochemical methods verified that 6y bound to MYOF. Mechanism studies revealed that 6y inhibited pancreatic cancer metastasis through reversing the epithelial mesenchymal transition, inhibiting the secretions of matrix metalloproteinase and blocking the receptor tyrosine kinases. Our findings suggest that targeting MYOF with 6y may be a promising therapeutic strategy to prevent pancreatic cancer metastasis. |
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| AbstractList | Pancreatic cancer is one of the most common cancers with an extremely low survival rate. Metastasis, as one of the key reasons of cancer-related death, is found in more than 50% pancreatic cancer patients at diagnosis. Novel therapeutic targets and drugs blocking cancer metastasis are urgently needed. Herein, we report a series of 1,5-diaryl-1,2,4-triazole derivatives as potent antimetastatic agents. Lead compound 6y displayed effective antimetastatic activities in pancreatic cancer in vitro and in vivo. Concomitant studies indicated that 6y probably binds with myoferlin (MYOF), a novel potential antitumor metastasis target, which regulates vesicle trafficking and metastasis-related proteins. Subsequent biophysical and biochemical methods verified that 6y bound to MYOF. Mechanism studies revealed that 6y inhibited pancreatic cancer metastasis through reversing the epithelial mesenchymal transition, inhibiting the secretions of matrix metalloproteinase and blocking the receptor tyrosine kinases. Our findings suggest that targeting MYOF with 6y may be a promising therapeutic strategy to prevent pancreatic cancer metastasis. Pancreatic cancer is one of the most common cancers with an extremely low survival rate. Metastasis, as one of the key reasons of cancer-related death, is found in more than 50% pancreatic cancer patients at diagnosis. Novel therapeutic targets and drugs blocking cancer metastasis are urgently needed. Herein, we report a series of 1,5-diaryl-1,2,4-triazole derivatives as potent antimetastatic agents. Lead compound 6y displayed effective antimetastatic activities in pancreatic cancer in vitro and in vivo. Concomitant studies indicated that 6y probably binds with myoferlin (MYOF), a novel potential antitumor metastasis target, which regulates vesicle trafficking and metastasis-related proteins. Subsequent biophysical and biochemical methods verified that 6y bound to MYOF. Mechanism studies revealed that 6y inhibited pancreatic cancer metastasis through reversing the epithelial mesenchymal transition, inhibiting the secretions of matrix metalloproteinase and blocking the receptor tyrosine kinases. Our findings suggest that that targeting MYOF with 6y may be a promising therapeutic strategy to prevent pancreatic cancer metastasis. |
| Author | Wang, Xin Shao, Ting Liu, Mingyao Wang, Peili Pei, Haixiang Li, Yunqi Mi, Dazhao Chen, Yihua Yi, Zhengfang He, Yuan Guo, Weikai Krimm, Isabelle Zhang, Yuanjin |
| AuthorAffiliation | Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences Joint Center for Translational Medicine Fengxian District Central Hospital |
| AuthorAffiliation_xml | – name: Fengxian District Central Hospital – name: Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences – name: Joint Center for Translational Medicine |
| Author_xml | – sequence: 1 givenname: Yunqi orcidid: 0000-0002-2841-1253 surname: Li fullname: Li, Yunqi organization: Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences – sequence: 2 givenname: Yuan orcidid: 0000-0001-8340-0875 surname: He fullname: He, Yuan organization: Fengxian District Central Hospital – sequence: 3 givenname: Ting orcidid: 0000-0001-5940-3777 surname: Shao fullname: Shao, Ting organization: Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences – sequence: 4 givenname: Haixiang orcidid: 0000-0002-5100-6950 surname: Pei fullname: Pei, Haixiang organization: Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences – sequence: 5 givenname: Weikai orcidid: 0000-0001-9361-3903 surname: Guo fullname: Guo, Weikai organization: Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences – sequence: 6 givenname: Dazhao orcidid: 0000-0002-1385-8917 surname: Mi fullname: Mi, Dazhao organization: Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences – sequence: 7 givenname: Isabelle orcidid: 0000-0002-5981-109X surname: Krimm fullname: Krimm, Isabelle – sequence: 8 givenname: Yuanjin orcidid: 0000-0001-7103-2059 surname: Zhang fullname: Zhang, Yuanjin organization: Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences – sequence: 9 givenname: Peili orcidid: 0000-0002-3179-8364 surname: Wang fullname: Wang, Peili organization: Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences – sequence: 10 givenname: Xin orcidid: 0000-0001-8079-8638 surname: Wang fullname: Wang, Xin organization: Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences – sequence: 11 givenname: Mingyao orcidid: 0000-0001-7339-5048 surname: Liu fullname: Liu, Mingyao email: myliu@bio.ecnu.edu.cn organization: Fengxian District Central Hospital – sequence: 12 givenname: Zhengfang orcidid: 0000-0003-3592-9912 surname: Yi fullname: Yi, Zhengfang email: zfyi@bio.ecnu.edu.cn organization: Fengxian District Central Hospital – sequence: 13 givenname: Yihua orcidid: 0000-0003-1733-7980 surname: Chen fullname: Chen, Yihua email: yhchen@bio.ecnu.edu.cn organization: Fengxian District Central Hospital |
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| Snippet | Pancreatic cancer is one of the most common cancers with an extremely low survival rate. Metastasis, as one of the key reasons of cancer-related death, is... |
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| Title | Modification and Biological Evaluation of a Series of 1,5-Diaryl-1,2,4-triazole Compounds as Novel Agents against Pancreatic Cancer Metastasis through Targeting Myoferlin |
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