"Design, synthesis and biological evaluation of 2,4-pyrimidinediamine derivatives as ALK and HDACs dual inhibitors for the treatment of ALK addicted cancer"

作者全名："Guo, Dafeng; Yu, Yu; Long, Binyu; Deng, Ping; Ran, Dongzhi; Han, Lei; Zheng, Jiecheng; Gan, Zongjie"

作者地址："[Guo, Dafeng; Yu, Yu; Long, Binyu; Deng, Ping; Ran, Dongzhi; Han, Lei; Zheng, Jiecheng; Gan, Zongjie] Chongqing Med Univ, Coll Pharm, Dept Med Chem, Chongqing 400016, Peoples R China; [Yu, Yu; Deng, Ping; Zheng, Jiecheng; Gan, Zongjie] Chongqing Med Univ, Chongqing Res Ctr Pharmaceut Engn, Chongqing, Peoples R China"

通信作者："Gan, ZJ (通讯作者)，Chongqing Med Univ, Coll Pharm, Dept Med Chem, Chongqing 400016, Peoples R China."

来源：JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:000853479500001

JCR分区：Q1

影响因子：5.6

年份：2022

卷号：37

期号：1

开始页：2512

结束页：2529

文献类型：Article

关键词：ALK; HDACs; dual inhibitors; 2; 4-pyrimidinediamine; ALK addicted

摘要："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 ALK(wt) 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."

基金机构："National Natural Science Foundation of China [21907013, 81172097]; Scientific and Technological Research Program of Chongqing Municipal Education Commission [KJQN201900431]"

基金资助正文："We appreciate the financial support from National Natural Science Foundation of China [No. 21907013, and No. 81172097] and the Scientific and Technological Research Program of Chongqing Municipal Education Commission [KJQN201900431]."