title: An integrated approach for discovery of highly potent and selective Mnk inhibitors: Screening, synthesis and SAR analysis.
abstract: Deregulation of protein synthesis is a common event in cancer. As MAPK-interacting kinases (Mnks) play critical roles in regulation of protein synthesis, they have emerged as novel anti-cancer targets. Mnks phosphorylate eukaryotic initiation factor 4E (eIF4E) and promote eIF4E-mediated oncogenic activity. Given that the kinase activity of Mnks is essential for oncogenesis but is dispensable for normal development, the discovery of potent and selective pharmacological Mnk inhibitors provides pharmacological target validation and offers a new strategy for cancer treatment. Herein, comprehensive in silico screening approaches were deployed, and three thieno[2,3-d]pyrimidine and pyrazolo[3,4-d]pyrimidine derivatives were identified as hit compounds. Further chemical modification of thieno[2,3-d]pyrimidine derivative 3 has given rise to a series of highly potent Mnk2 inhibitors that could be potential leads for the treatment of acute myeloid leukemia.
authors.affiliation: Center for Drug Discovery and Development, Sansom Institute for Health Research, Center for Cancer Biology, and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
authors.forename: Theodosia
authors.initials: T
authors.lastname: Teo
authors.affiliation: Center for Drug Discovery and Development, Sansom Institute for Health Research, Center for Cancer Biology, and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
authors.forename: Yuchao
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Center for Drug Discovery and Development, Sansom Institute for Health Research, Center for Cancer Biology, and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Yu
authors.affiliation: Center for Drug Discovery and Development, Sansom Institute for Health Research, Center for Cancer Biology, and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
authors.forename: Sunita K C
authors.initials: SK
authors.lastname: Basnet
authors.affiliation: Center for Drug Discovery and Development, Sansom Institute for Health Research, Center for Cancer Biology, and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
authors.forename: Todd
authors.initials: T
authors.lastname: Gillam
authors.affiliation: Center for Drug Discovery and Development, Sansom Institute for Health Research, Center for Cancer Biology, and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
authors.forename: Jinqiang
authors.initials: J
authors.lastname: Hou
authors.affiliation: Center for Drug Discovery and Development, Sansom Institute for Health Research, Center for Cancer Biology, and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
authors.forename: Raffaella M
authors.initials: RM
authors.lastname: Schmid
authors.affiliation: Center for Drug Discovery and Development, Sansom Institute for Health Research, Center for Cancer Biology, and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
authors.forename: Malika
authors.initials: M
authors.lastname: Kumarasiri
authors.affiliation: Center for Drug Discovery and Development, Sansom Institute for Health Research, Center for Cancer Biology, and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Diab
authors.affiliation: Center for Drug Discovery and Development, Sansom Institute for Health Research, Center for Cancer Biology, and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
authors.forename: Hugo
authors.initials: H
authors.lastname: Albrecht
authors.affiliation: Center for Drug Discovery and Development, Sansom Institute for Health Research, Center for Cancer Biology, and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sykes
authors.affiliation: Center for Drug Discovery and Development, Sansom Institute for Health Research, Center for Cancer Biology, and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia. Electronic address: shudong.wang@unisa.edu.au.
authors.forename: Shudong
authors.initials: S
authors.lastname: Wang
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; 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; D013329:Structure-Activity Relationship
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; C491395:MKNK1 protein, human; C486342:MKNK2 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: CGP57380; Eukaryotic initiation factor 4E; Mnk inhibitors; Structure-activity relationship; Thieno[2,3-d]pyrimidine; Virtual screening