title: EW-7197, a novel ALK-5 kinase inhibitor, potently inhibits breast to lung metastasis.
abstract: Advanced tumors produce an excessive amount of transforming growth factor β (TGFβ), which promotes tumor progression at late stages of malignancy. The purpose of this study was to develop anti-TGFβ therapeutics for cancer. We synthesized a novel small-molecule TGFβ receptor I kinase (activin receptor-like kinase 5) inhibitor termed N-[[4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl]methyl]-2-fluoroaniline (EW-7197), and we investigated its potential antimetastatic efficacy in mouse mammary tumor virus (MMTV)/c-Neu mice and 4T1 orthotopic-grafted mice. EW-7197 inhibited Smad/TGFβ signaling, cell migration, invasion, and lung metastasis in MMTV/c-Neu mice and 4T1 orthotopic-grafted mice. EW-7197 also inhibited the epithelial-to-mesenchymal transition (EMT) in both TGFβ-treated breast cancer cells and 4T1 orthotopic-grafted mice. Furthermore, EW-7197 enhanced cytotoxic T lymphocyte activity in 4T1 orthotopic-grafted mice and increased the survival time of 4T1-Luc and 4T1 breast tumor-bearing mice. In summary, EW-7197 showed potent in vivo antimetastatic activity, indicating its potential for use as an anticancer therapy.
authors.affiliation: Authors' Affiliations: College of Pharmacy, Ewha Womans University, Seodaemun-gu, Seoul; and.
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Son
authors.affiliation: Authors' Affiliations: College of Pharmacy, Ewha Womans University, Seodaemun-gu, Seoul; and.
authors.forename: So-Yeon
authors.initials: SY
authors.lastname: Park
authors.affiliation: Authors' Affiliations: College of Pharmacy, Ewha Womans University, Seodaemun-gu, Seoul; and.
authors.forename: Sol-Ji
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Authors' Affiliations: College of Pharmacy, Ewha Womans University, Seodaemun-gu, Seoul; and.
authors.forename: Seon Joo
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Authors' Affiliations: College of Pharmacy, Ewha Womans University, Seodaemun-gu, Seoul; and.
authors.forename: Sang-A
authors.initials: SA
authors.lastname: Park
authors.affiliation: Authors' Affiliations: College of Pharmacy, Ewha Womans University, Seodaemun-gu, Seoul; and.
authors.forename: Min-Jin
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Authors' Affiliations: College of Pharmacy, Ewha Womans University, Seodaemun-gu, Seoul; and.
authors.forename: Seung Won
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Authors' Affiliations: College of Pharmacy, Ewha Womans University, Seodaemun-gu, Seoul; and.
authors.forename: Dae-Kee
authors.initials: DK
authors.lastname: Kim
authors.affiliation: Laboratory of Tumor Suppressor, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, South Korea yysheen@ewha.ac.kr namjs@gachon.ac.kr.
authors.forename: Jeong-Seok
authors.initials: JS
authors.lastname: Nam
authors.affiliation: Authors' Affiliations: College of Pharmacy, Ewha Womans University, Seodaemun-gu, Seoul; and yysheen@ewha.ac.kr namjs@gachon.ac.kr.
authors.forename: Yhun Yhong
authors.initials: YY
authors.lastname: Sheen
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000517:prevention & control* / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011897:Random Allocation; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000814:Aniline Compounds; D047428:Protein Kinase Inhibitors; D018125:Receptors, Transforming Growth Factor beta; D014230:Triazoles; C000590371:vactosertib; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse