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

Dafeng Guo; Yu Yu; Binyu Long; Ping Deng; Dongzhi Ran; Lei Han; Jiecheng Zheng; Zongjie Gan

doi:10.1080/14756366.2022.2121822

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

J Enzyme Inhib Med Chem. 2022 Dec;37(1):2512-2529. doi: 10.1080/14756366.2022.2121822.

Authors

Dafeng Guo¹, Yu Yu^{1

2}, Binyu Long¹, Ping Deng^{1

2}, Dongzhi Ran¹, Lei Han¹, Jiecheng Zheng^{1

2}, Zongjie Gan^{1

2}

Affiliations

¹ Department of Medicinal Chemistry, College of Pharmacy, Chongqing Medical University, Chongqing, PR China.
² Chongqing Research Center for Pharmaceutical Engineering, Chongqing Medical University, Chongqing, PR China.

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 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.

Keywords: 2,4-pyrimidinediamine; ALK; ALK addicted; HDACs; dual inhibitors.

MeSH terms

Anaplastic Lymphoma Kinase
Apoptosis
Cell Line, Tumor
Histone Deacetylase Inhibitors* / pharmacology
Histone Deacetylases
Neoplasms*

Substances

Histone Deacetylase Inhibitors
Anaplastic Lymphoma Kinase
Histone Deacetylases

Grants and funding

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].