title: A novel aminothiazole KY-05009 with potential to inhibit Traf2- and Nck-interacting kinase (TNIK) attenuates TGF-β1-mediated epithelial-to-mesenchymal transition in human lung adenocarcinoma A549 cells.
abstract: Transforming growth factor (TGF)-β triggers the epithelial-to-mesenchymal transition (EMT) of cancer cells via well-orchestrated crosstalk between Smad and non-Smad signaling pathways, including Wnt/β-catenin. Since EMT-induced motility and invasion play a critical role in cancer metastasis, EMT-related molecules are emerging as novel targets of anti-cancer therapies. Traf2- and Nck-interacting kinase (TNIK) has recently been considered as a first-in-class anti-cancer target molecule to regulate Wnt signaling pathway, but pharmacologic inhibition of its EMT activity has not yet been studied. Here, using 5-(4-methylbenzamido)-2-(phenylamino)thiazole-4-carboxamide (KY-05009) with TNIK-inhibitory activity, its efficacy to inhibit EMT in cancer cells was validated. The molecular docking/binding study revealed the binding of KY-05009 in the hinge region of TNIK, and the inhibitory activity of KY-05009 against TNIK was confirmed by an ATP competition assay (Ki, 100 nM). In A549 cells, KY-05009 significantly and strongly inhibited the TGF-β-activated EMT through the attenuation of Smad and non-Smad signaling pathways, including the Wnt, NF-κB, FAK-Src-paxillin-related focal adhesion, and MAP kinases (ERK and JNK) signaling pathways. Continuing efforts to identify and validate potential therapeutic targets associated with EMT, such as TNIK, provide new and improved therapies for treating and/or preventing EMT-based disorders, such as cancer metastasis and fibrosis.
authors.affiliation: Department of Biomedical Laboratory Science, School of Medicine, Eulji University, Jung-gu, Daejeon, Republic of Korea.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Kim
authors.affiliation: Laboratory of Translational Therapeutics, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon, Republic of Korea.
authors.forename: Seong-Hee
authors.initials: SH
authors.lastname: Moon
authors.affiliation: Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon, Republic of Korea.
authors.forename: Bum Tae
authors.initials: BT
authors.lastname: Kim
authors.affiliation: Drug Discovery Platform Technology Team, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon, Republic of Korea.
authors.forename: Chong Hak
authors.initials: CH
authors.lastname: Chae
authors.affiliation: Drug Discovery Platform Technology Team, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon, Republic of Korea.
authors.forename: Joo Yun
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Laboratory of Translational Therapeutics, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon, Republic of Korea.
authors.forename: Seong Hwan
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D000081410:Germinal Center Kinases; D006801:Humans; D062105:Molecular Docking Simulation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C000598870:5-(4-methylbenzamido)-2-(phenylamino)thiazole-4-carboxamide; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D000081410:Germinal Center Kinases; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D051785:Smad Proteins; D013844:Thiazoles; D053773:Transforming Growth Factor beta1; D051153:Wnt Proteins; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D019061:src-Family Kinases; D017346:Protein Serine-Threonine Kinases; C000631454:TNIK protein, human; D048049:Extracellular Signal-Regulated MAP Kinases