title: The mTOR Kinase Inhibitor INK128 Blunts Migration of Cultured Retinal Pigment Epithelial Cells.
abstract: Retinal pigment epithelium (RPE) cell migration in response to disease has been reported for age-related macular degeneration, proliferative vitreoretinopathy, and proliferative diabetic retinopathy. The complex molecular process of RPE cell migration is regulated in part by growth factors and cytokines, and activation of the PI3/AKT/mTOR signaling pathway. Rapamycin, an allosteric mTOR inhibitor, has been shown to block only one of the primary downstream mTOR effectors, p70 S6 kinase 1, in many cell types. INK128, a selective mTOR ATP binding site competitor, blocks both p70 S6 kinase 1 and a second primary downstream effector, 4E-BP1. We performed scratch assays using differentiated ARPE-19 and primary porcine RPE cells to assess the effect of mTOR inhibition on cell migration. We found that INK128-mediated blocking of both p70 S6 kinase 1 and 4E-BP1 was much more effective at preventing RPE cell migration than rapamycin-mediated inhibition of p70 S6 kinase 1 alone.
authors.affiliation: Department of Genetics, Stanford University School of Medicine, 94305-5120, Stanford, CA, USA. macalton@stanford.edu.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Calton
authors.affiliation: Department of Genetics, Stanford University School of Medicine, 94305-5120, Stanford, CA, USA. vollrath@stanford.edu.
authors.forename: Douglas
authors.initials: D
authors.lastname: Vollrath
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D055213:Retinal Pigment Epithelium / Q000166:cytology*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D013552:Swine; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000225:Adenine / Q000031:analogs & derivatives
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001583:Benzoxazoles; D018797:Cell Cycle Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C087000:EIF4EBP1 protein, human; C546842:MTOR protein, human; C572449:sapanisertib; D000225:Adenine
keywords: ARPE-19; Age-related macular degeneration; INK128; MTOR; Migration; Proliferative vitreoretinopathy; Rapamycin; Retinal pigment epithelium