title: Unveiling new chemical scaffolds as Mnk inhibitors.
abstract: The discovery of small molecules that selectively inhibit Mnks is considered of paramount importance towards deciphering the exact role of these proteins in carcinogenesis and to further validate them as anti-cancer drug targets. However, the dearth of structural information of Mnks is a major hurdle. This study unveils the 7H-pyrrolo[2,3-d]pyrimidine derivatives as potent inhibitors of Mnks. ATP and substrate competition assays showed that this scaffold interacts with the ATP binding site, but not with the substrate site. Screened against a panel of cancer cells, Mnk inhibitors were most potent against MV4-11 acute myeloid leukemia cells. The induction of apoptosis was shown to be mediated by downregulation of Mcl-1.
authors.affiliation: Centre for Drug Discovery & Development, Sansom Institute for Health Research, Centre for Cancer Biology, School of Pharmacy & Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Diab
authors.affiliation: Centre for Drug Discovery & Development, Sansom Institute for Health Research, Centre for Cancer Biology, School of Pharmacy & Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: Centre for Drug Discovery & Development, Sansom Institute for Health Research, Centre for Cancer Biology, School of Pharmacy & Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
authors.forename: Sunita K C
authors.initials: SK
authors.lastname: Basnet
authors.affiliation: Centre for Drug Discovery & Development, Sansom Institute for Health Research, Centre for Cancer Biology, School of Pharmacy & Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
authors.forename: Jingfeng
authors.initials: J
authors.lastname: Lu
authors.affiliation: Centre for Drug Discovery & Development, Sansom Institute for Health Research, Centre for Cancer Biology, School of Pharmacy & Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Yu
authors.affiliation: Centre for Drug Discovery & Development, Sansom Institute for Health Research, Centre for Cancer Biology, School of Pharmacy & Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
authors.forename: Hugo
authors.initials: H
authors.lastname: Albrecht
authors.affiliation: Centre for Drug Discovery & Development, Sansom Institute for Health Research, Centre for Cancer Biology, School of Pharmacy & Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Milne
authors.affiliation: Centre for Drug Discovery & Development, Sansom Institute for Health Research, Centre for Cancer Biology, School of Pharmacy & Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
authors.forename: Shudong
authors.initials: S
authors.lastname: Wang
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000073840:Copper-Transporting ATPases; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D004791:Enzyme Inhibitors; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases
keywords: AML; CGP57380; Mnk kinase inhibitors; anti-cancer drug discovery; eIF4E phosphorylation