Design, Synthesis, and Biological Evaluation of 2-Anilino-4-Triazolpyrimidine Derivatives as CDK4/HDACs Inhibitors

Suhua Wang; Siyuan Han; Weiyan Cheng; Ruoyang Miao; Shasha Li; Xin Tian; Quancheng Kan

doi:10.2147/DDDT.S351049

Design, Synthesis, and Biological Evaluation of 2-Anilino-4-Triazolpyrimidine Derivatives as CDK4/HDACs Inhibitors

Drug Des Devel Ther. 2022 Apr 11:16:1083-1097. doi: 10.2147/DDDT.S351049. eCollection 2022.

Authors

Suhua Wang^{1

2}, Siyuan Han^{1

2}, Weiyan Cheng^{1

2}, Ruoyang Miao^{1

2}, Shasha Li^{1

2}, Xin Tian^{1

2}, Quancheng Kan^{1

2}

Affiliations

¹ Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People's Republic of China.
² Henan Key Laboratory of Precision Clinical Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People's Republic of China.

Abstract

Purpose: To enhance the cytotoxicities of our obtained CDK4 inhibitors and get CDK4/HDACs inhibitors with potent enzymatic inhibitory and anti-proliferative activities.

Methods: A series of novel CDK4/HDACs inhibitors were designed and synthesized by incorporating the HDAC pharmacophores (hydroxylamine or o-diaminoaniline) into the basic structure of our newly obtained 2-anilino-4-triazolpyrimidine based CDK4 inhibitors. The enzymatic inhibitory (HDAC1, CDK2, CDK4, and CDK6) activities and cytotoxicities of these compounds were evaluated. Moreover, HDAC isoforms inhibitory activity, cell cycle arrest assay, cell apoptosis analysis, cell migration, and cell colony formation assay were performed for the representative compound 11k.

Results: Most of these compounds showed excellent HDAC1 inhibitory activities (IC_50s: 0.68~244.5 nM) and anti-proliferative activities against cancer cell lines. Some compounds displayed potent CDK4 inhibitory activities and a certain selectivity towards CDK2 and CDK6. Compound 11k exhibited potent enzymatic (CDK4: IC₅₀=23.59 nM; HDAC1: IC₅₀=61.11 nM; HDAC2: IC₅₀=80.62 nM; HDAC6: IC₅₀=45.33 nM) and anti-proliferative activities against H460, MDA-MB-468, HCT116, and HepG2 cell lines with IC₅₀ values 1.20, 1.34, 2.07, and 2.66 μM, respectively. Further mechanistic studies revealed that compound 11k could arrest the cell cycle in G0/G1 phase and induce apoptosis in HCT116 and MDA-MB-468 cells. In addition, compound 11k significantly inhibited the migration and cell colony formation of H460 and HCT116 cells.

Conclusion: This study suggested that the incorporation of the HDAC pharmacophore into CDK4 inhibitor scaffold to design CDK/HDAC inhibitors might be a tractable strategy to enhance the antitumor potency of compounds.

Keywords: 2-anilino-4-triazolpyrimidine; CDK4; HDAC; cancer; inhibitor.

MeSH terms

Antineoplastic Agents* / chemistry
Cell Line, Tumor
Cell Proliferation
Cyclin-Dependent Kinase 4 / metabolism
Drug Design*
Drug Screening Assays, Antitumor
Histone Deacetylase Inhibitors / chemistry
Histone Deacetylases / metabolism
Humans
Molecular Docking Simulation
Molecular Structure
Structure-Activity Relationship

Substances

Antineoplastic Agents
Histone Deacetylase Inhibitors
CDK4 protein, human
Cyclin-Dependent Kinase 4
Histone Deacetylases

Grants and funding

We gratefully acknowledge the funding supports of grants from Major Science and Technology Project of Henan Province (161100311000), National Natural Science Foundation of China (31870809 and 32170594), and the Medical Science and Technology Project of Health Commission of Henan Province (2018020039).