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

ABSTRACT: 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.

SUBMITTER: Guo D 

PROVIDER: S-EPMC9481106 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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

Guo Dafeng D   Yu Yu Y   Long Binyu B   Deng Ping P   Ran Dongzhi D   Han Lei L   Zheng Jiecheng J   Gan Zongjie Z  

Journal of enzyme inhibition and medicinal chemistry 20221201 1

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 <b>12a</b> which possessed good inhibitory potency against ALK<sup>wt</sup> and HDAC1, exhibited stronger antiproliferative activity than Ceritinib on ALK positive cancer cell lines though induci  ...[more]

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