Design, synthesis and biological evaluation of 2,4-pyrimidinediamine derivatives as ALK and HDACs dual inhibitors for the treatment of ALK addicted cancer
Simultaneous inhibition of histone deacetylases (HDACs) and anaplastic lymphoma kinase (ALK) could enhance therapeutic activity against ALK addicted cancer cells. Herein, a new series of 2,4-pyrimidinediamine derivatives as ALK and HDACs dual inhibitors were designed, synthesised and evaluated. Comp...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2022-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2022.2121822 |
| _version_ | 1798033303952949248 |
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| author | Dafeng Guo Yu Yu Binyu Long Ping Deng Dongzhi Ran Lei Han Jiecheng Zheng Zongjie Gan |
| author_facet | Dafeng Guo Yu Yu Binyu Long Ping Deng Dongzhi Ran Lei Han Jiecheng Zheng Zongjie Gan |
| author_sort | Dafeng Guo |
| collection | DOAJ |
| description | Simultaneous inhibition of histone deacetylases (HDACs) and anaplastic lymphoma kinase (ALK) could enhance therapeutic activity against ALK addicted cancer cells. Herein, a new series of 2,4-pyrimidinediamine derivatives as ALK and HDACs dual inhibitors were designed, synthesised and evaluated. Compound 12a which possessed good inhibitory potency against ALKwt and HDAC1, exhibited stronger antiproliferative activity than Ceritinib on ALK positive cancer cell lines though inducing cell apoptosis and cell cycle arrest in vitro and in vivo. In addition, the mechanism is further verified by the down-regulation of p-ALK protein, and up-regulation of Acetylated histone 3 (Ac-H3) protein in cancer cells. These results suggested that 12a would be a potential candidate for the ALK addicted cancer treatment. |
| first_indexed | 2024-04-11T20:28:10Z |
| format | Article |
| id | doaj.art-71b55731c97b44d4b874f53ec9623f18 |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-04-11T20:28:10Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-71b55731c97b44d4b874f53ec9623f182022-12-22T04:04:36ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742022-12-013712512252910.1080/14756366.2022.2121822Design, synthesis and biological evaluation of 2,4-pyrimidinediamine derivatives as ALK and HDACs dual inhibitors for the treatment of ALK addicted cancerDafeng Guo0Yu Yu1Binyu Long2Ping Deng3Dongzhi Ran4Lei Han5Jiecheng Zheng6Zongjie Gan7Department of Medicinal Chemistry, College of Pharmacy, Chongqing Medical University, Chongqing, PR ChinaDepartment of Medicinal Chemistry, College of Pharmacy, Chongqing Medical University, Chongqing, PR ChinaDepartment of Medicinal Chemistry, College of Pharmacy, Chongqing Medical University, Chongqing, PR ChinaDepartment of Medicinal Chemistry, College of Pharmacy, Chongqing Medical University, Chongqing, PR ChinaDepartment of Medicinal Chemistry, College of Pharmacy, Chongqing Medical University, Chongqing, PR ChinaDepartment of Medicinal Chemistry, College of Pharmacy, Chongqing Medical University, Chongqing, PR ChinaDepartment of Medicinal Chemistry, College of Pharmacy, Chongqing Medical University, Chongqing, PR ChinaDepartment of Medicinal Chemistry, College of Pharmacy, Chongqing Medical University, Chongqing, PR ChinaSimultaneous inhibition of histone deacetylases (HDACs) and anaplastic lymphoma kinase (ALK) could enhance therapeutic activity against ALK addicted cancer cells. Herein, a new series of 2,4-pyrimidinediamine derivatives as ALK and HDACs dual inhibitors were designed, synthesised and evaluated. Compound 12a which possessed good inhibitory potency against ALKwt and HDAC1, exhibited stronger antiproliferative activity than Ceritinib on ALK positive cancer cell lines though inducing cell apoptosis and cell cycle arrest in vitro and in vivo. In addition, the mechanism is further verified by the down-regulation of p-ALK protein, and up-regulation of Acetylated histone 3 (Ac-H3) protein in cancer cells. These results suggested that 12a would be a potential candidate for the ALK addicted cancer treatment.https://www.tandfonline.com/doi/10.1080/14756366.2022.2121822ALKHDACsdual inhibitors2,4-pyrimidinediamineALK addicted |
| spellingShingle | Dafeng Guo Yu Yu Binyu Long Ping Deng Dongzhi Ran Lei Han Jiecheng Zheng Zongjie Gan Design, synthesis and biological evaluation of 2,4-pyrimidinediamine derivatives as ALK and HDACs dual inhibitors for the treatment of ALK addicted cancer Journal of Enzyme Inhibition and Medicinal Chemistry ALK HDACs dual inhibitors 2,4-pyrimidinediamine ALK addicted |
| title | Design, synthesis and biological evaluation of 2,4-pyrimidinediamine derivatives as ALK and HDACs dual inhibitors for the treatment of ALK addicted cancer |
| title_full | Design, synthesis and biological evaluation of 2,4-pyrimidinediamine derivatives as ALK and HDACs dual inhibitors for the treatment of ALK addicted cancer |
| title_fullStr | Design, synthesis and biological evaluation of 2,4-pyrimidinediamine derivatives as ALK and HDACs dual inhibitors for the treatment of ALK addicted cancer |
| title_full_unstemmed | Design, synthesis and biological evaluation of 2,4-pyrimidinediamine derivatives as ALK and HDACs dual inhibitors for the treatment of ALK addicted cancer |
| title_short | Design, synthesis and biological evaluation of 2,4-pyrimidinediamine derivatives as ALK and HDACs dual inhibitors for the treatment of ALK addicted cancer |
| title_sort | design synthesis and biological evaluation of 2 4 pyrimidinediamine derivatives as alk and hdacs dual inhibitors for the treatment of alk addicted cancer |
| topic | ALK HDACs dual inhibitors 2,4-pyrimidinediamine ALK addicted |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2022.2121822 |
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