Design, synthesis and biological evaluation of 2,4-pyrimidinediamine derivatives as ALK and HDACs dual inhibitors for the treatment of ALK addicted cancer.
Design, synthesis and biological evaluation of 2,4-pyrimidinediamine derivatives as ALK and HDACs dual inhibitors for the treatment of ALK addicted cancer.
复制标题
DOI：
10.1080/14756366.2022.2121822
复制
发表时间：
2022-12
影响因子：
5.6
通讯作者：
Gan Z
中科院分区：
文献类型：
--
作者：
Guo D;Yu Y;Long B;Deng P;Ran D;Han L;Zheng J;Gan Z
同时抑制组蛋白脱乙酰酶(HDACs)和间变性淋巴瘤激酶(ALK)可增强对ALK成瘾癌细胞的治疗活性。本论文设计、合成并评价了一系列新型的2，4-嘧啶二胺类化合物作为ALK和HDACs的双重抑制剂。化合物12A对ALKut和HDAC1具有良好的抑制活性，在体内外对ALK阳性癌细胞株的抗增殖活性明显强于Ceritinib，可诱导细胞凋亡和细胞周期停滞。此外，肿瘤细胞中p-ALK蛋白下调和乙酰化组蛋白3(Ac-H3)蛋白上调进一步验证了其作用机制。这些结果表明，12A可能是治疗ALK成瘾癌症的潜在候选者。
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.
登录
查看更多内容
影响因子：
5.4
作者：
Li Y;Seto E
通讯作者：
Seto E
影响因子：
3.3
作者：
Prince, H. Miles;Bishton, Mark J.;Johnstone, Ricky W.
通讯作者：
Johnstone, Ricky W.
影响因子：
2
作者：
Hagiwara, Kazumi;Tokunaga, Takashi;Nagai, Hirokazu
通讯作者：
Nagai, Hirokazu
影响因子：
11.2
作者：
Yun, Mi Ran;Lim, Sun Min;Cho, Byoung Chul
通讯作者：
Cho, Byoung Chul
影响因子：
4.6
作者：
Gristina V;La Mantia M;Iacono F;Galvano A;Russo A;Bazan V
通讯作者：
Bazan V