title: Discovery of 5-(2-(phenylamino)pyrimidin-4-yl)thiazol-2(3H)-one derivatives as potent Mnk2 inhibitors: synthesis, SAR analysis and biological evaluation.
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.
authors.affiliation: 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).
authors.forename: Sarah
authors.initials: S
authors.lastname: Diab
authors.forename: Theodosia
authors.initials: T
authors.lastname: Teo
authors.forename: Malika
authors.initials: M
authors.lastname: Kumarasiri
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Yu
authors.forename: Frankie
authors.initials: F
authors.lastname: Lam
authors.forename: Sunita K C
authors.initials: SK
authors.lastname: Basnet
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sykes
authors.forename: Hugo
authors.initials: H
authors.lastname: Albrecht
authors.forename: Robert
authors.initials: R
authors.lastname: Milne
authors.forename: Shudong
authors.initials: S
authors.lastname: Wang
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000473:pathology*; D061986:MCF-7 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011687:Purines / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; C466997:CGP 57380; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011687:Purines; D011743:Pyrimidines; D013844:Thiazoles; C486342:MKNK2 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: CGP57380; Mnk inhibitors; anticancer drug discovery; apoptosis; eIF4E phosphorylation