Design, synthesis and biological evaluation of imidazopyridazine derivatives containing isoquinoline group as potent MNK1/2 inhibitors

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

doi:10.1016/j.bmc.2021.116186

Design, synthesis and biological evaluation of imidazopyridazine derivatives containing isoquinoline group as potent MNK1/2 inhibitors

Bioorg Med Chem. 2021 Jun 15:40:116186. doi: 10.1016/j.bmc.2021.116186. Epub 2021 May 2.

Authors

Hong Bu¹, Xinrui Yuan¹, Hanshu Wu², 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: 33971490
DOI: 10.1016/j.bmc.2021.116186

Abstract

Mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) are located at the meeting-point of ERK and p38 MAPK signaling pathways, which can phosphorylate eukaryotic translation initiation factor 4E (eIF4E) at the conserved serine 209 exclusively. MNKs modulate the translation of mRNA involved in tumor-associated signaling pathways. Consequently, selective inhibitors of MNK1/2 could reduce the level of phosphorylated eIF4E. Series of imidazopyrazines, imidazopyridazines and imidazopyridines 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 diffuse large B-cell lymphoma (DLBCL) cell lines. In particular, compound II-5 (MNK1 IC50 = 2.3 nM; MNK2 IC50 = 3.4 nM) exhibited excellent enzymatic inhibitory potency and proved to be the most potent compound against TMD-8 and DOHH-2 cell lines with IC₅₀ value of 0.3896 μM and 0.4092 μM respectively. These results demonstrated that compound II-5 could be considered as a potential MNK1/2 inhibitor for further investigation.

Keywords: ETC-206; MNK1/2 kinases; MNKs inhibitor; eIF4E.

Publication types

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

MeSH terms

Dose-Response Relationship, Drug
Drug Design*
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry
Imidazoles / pharmacology*
Isoquinolines / chemistry
Isoquinolines / pharmacology*
MAP Kinase Kinase 1 / antagonists & inhibitors*
MAP Kinase Kinase 1 / metabolism
MAP Kinase Kinase 2 / antagonists & inhibitors*
MAP Kinase Kinase 2 / metabolism
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyridazines / chemical synthesis
Pyridazines / chemistry
Pyridazines / pharmacology*
Structure-Activity Relationship

Substances

Imidazoles
Isoquinolines
Protein Kinase Inhibitors
Pyridazines
MAP2K2 protein, human
MAP Kinase Kinase 1
MAP Kinase Kinase 2
MAP2K1 protein, human
isoquinoline