Design, synthesis and biological evaluation of pyridone-aminal derivatives as MNK1/2 inhibitors

Xinrui Yuan; Hanshu Wu; Hong Bu; Peiyuan Zheng; Jinpei Zhou; Huibin Zhang

doi:10.1016/j.bmc.2019.02.007

Design, synthesis and biological evaluation of pyridone-aminal derivatives as MNK1/2 inhibitors

Bioorg Med Chem. 2019 Apr 1;27(7):1211-1225. doi: 10.1016/j.bmc.2019.02.007. Epub 2019 Feb 2.

Authors

Xinrui Yuan¹, Hanshu Wu², Hong Bu¹, Peiyuan Zheng¹, Jinpei Zhou³, Huibin Zhang⁴

Affiliations

¹ Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
² Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
³ Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: jpzhou668@163.com.
⁴ Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: zhanghb80@cpu.edu.cn.

PMID: 30824167
DOI: 10.1016/j.bmc.2019.02.007

Abstract

Excessive phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) plays a major role in the dysregulation of mRNA translation and the activation of tumor cell signaling. eIF4E is exclusively phosphorylated by mitogen-activated protein kinase interacting kinases 1 and 2 (MNK1/2) on Ser209. So, MNK1/2 inhibitors could decrease the level of p-eIF4E and regulate tumor-associated signaling pathways. A series of pyridone-aminal derivatives were synthesized and evaluated as MNK1/2 inhibitors. Several compounds exhibited great inhibitory activity against MNK1/2 and selected compounds showed moderate to excellent anti-proliferative potency against hematologic cancer cell lines. In particular, compound 42i (MNK1 IC₅₀ = 7.0 nM; MNK2 IC₅₀ = 6.1 nM) proved to be the most potent compound against TMD-8 cell line with IC₅₀ value of 0.91 μM. Furthermore, 42i could block the phosphorylation level of eIF4E in CT-26 cell line, and 42i inhibited the tumor growth of CT-26 allograft model significantly. These results indicated that compound 42i was a promising MNK1/2 inhibitor for the potent treatment of colon cancer.

Keywords: MNK1/2; Pyridone–aminal; eFT508; eIF4E.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amines / chemistry
Amines / pharmacology*
Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design
Drug Screening Assays, Antitumor
Humans
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
Intracellular Signaling Peptides and Proteins / metabolism
Male
Mice
Mice, Inbred BALB C
Molecular Docking Simulation
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / metabolism
Neoplasms, Experimental / pathology
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / metabolism
Pyridones / chemistry
Pyridones / pharmacology*
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Amines
Antineoplastic Agents
Intracellular Signaling Peptides and Proteins
Protein Kinase Inhibitors
Pyridones
MKNK1 protein, human
MKNK2 protein, human
Protein Serine-Threonine Kinases