Discovery of 5-(2-(phenylamino)pyrimidin-4-yl)thiazol-2(3H)-one derivatives as potent Mnk2 inhibitors: synthesis, SAR analysis and biological evaluation

Sarah Diab; Theodosia Teo; Malika Kumarasiri; Peng Li; Mingfeng Yu; Frankie Lam; Sunita K C Basnet; Matthew J Sykes; Hugo Albrecht; Robert Milne; Shudong Wang

doi:10.1002/cmdc.201300552

Discovery of 5-(2-(phenylamino)pyrimidin-4-yl)thiazol-2(3H)-one derivatives as potent Mnk2 inhibitors: synthesis, SAR analysis and biological evaluation

ChemMedChem. 2014 May;9(5):962-72. doi: 10.1002/cmdc.201300552. Epub 2014 Feb 12.

Authors

Sarah Diab¹, Theodosia Teo, Malika Kumarasiri, Peng Li, Mingfeng Yu, Frankie Lam, Sunita K C Basnet, Matthew J Sykes, Hugo Albrecht, Robert Milne, Shudong Wang

Affiliation

¹ Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001 (Australia).

PMID: 24677692
DOI: 10.1002/cmdc.201300552

Abstract

Phosphorylation of eIF4E by human mitogen-activated protein kinase (MAPK)-interacting kinases (Mnks) is crucial for human tumourigenesis and development. Targeting Mnks may provide a novel anticancer therapeutic strategy. However, the lack of selective Mnk inhibitors has so far hampered pharmacological target validation and clinical drug development. Herein, we report, for the first time, the discovery of a series of 5-(2-(phenylamino)pyrimidin-4-yl)thiazole-2(3H)-one derivatives as Mnk inhibitors. Several derivatives demonstrate very potent Mnk2 inhibitory activity. The most active and selective compounds were tested against a panel of cancer cell lines, and the results confirm the cell-type-specific effect of these Mnk inhibitors. Detailed cellular mechanistic studies reveal that Mnk inhibitors are capable of reducing the expression level of anti-apoptotic protein Mcl-1, and of promoting apoptosis in MV4-11 acute myeloid leukaemia cells.

Keywords: CGP57380; Mnk inhibitors; anticancer drug discovery; apoptosis; eIF4E phosphorylation.

Publication types

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

MeSH terms

Aniline Compounds / chemistry
Aniline Compounds / pharmacology
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
HCT116 Cells
Humans
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
Intracellular Signaling Peptides and Proteins / metabolism
Leukemia, Myeloid, Acute / drug therapy
Leukemia, Myeloid, Acute / pathology*
MCF-7 Cells
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / metabolism
Purines / chemistry
Purines / pharmacology
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship
Thiazoles / chemical synthesis
Thiazoles / chemistry
Thiazoles / pharmacology*

Substances

Aniline Compounds
Antineoplastic Agents
CGP 57380
Intracellular Signaling Peptides and Proteins
Protein Kinase Inhibitors
Purines
Pyrimidines
Thiazoles
MKNK2 protein, human
Protein Serine-Threonine Kinases