title: Pyridone 6, a pan-Janus-activated kinase inhibitor, induces growth inhibition of multiple myeloma cells.
abstract: Interleukin-6 (IL-6) and the subsequent Janus-activated kinase (JAK)-dependent signaling pathways play a critical role in the pathogenesis of multiple myeloma. Here, we compared the sensitivity and specificity of a novel pan-JAK inhibitor, tetracyclic pyridone 6 (P6), with that of AG490 in a panel of myeloma-derived cell lines. P6 induced growth arrest and subsequent apoptosis of the IL-6-dependent hybridoma and myeloma-derived cell lines (B9 and INA-6) grown either in IL-6-containing medium or in the presence of bone marrow-derived stromal cells (BMSC) using much lower concentrations of drug and with significantly faster kinetics than AG490. Myeloma-derived cell lines, which either express constitutively activated JAK/signal transducers and activators of transcription (STAT) 3 (U266) or are IL-6 growth stimulated (KMS11), are partially growth inhibited by P6. However, P6 does not inhibit the growth of myeloma-derived cell lines lacking activated JAKs/STATs nor does it inhibit mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase activity compared with AG490, which led to activation of ERK and induced robust apoptosis of all the examined cell lines. Finally, P6 inhibited the growth of primary myeloma patient samples grown in the presence of BMSCs. Thus, P6 is a more sensitive and specific inhibitor of JAK-STAT3 activity compared with AG490 and potently inhibited the growth of primary myeloma cells and myeloma-derived cell lines grown on BMSCs.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Pedranzini
authors.forename: Tobias
authors.initials: T
authors.lastname: Dechow
authors.forename: Marjan
authors.initials: M
authors.lastname: Berishaj
authors.forename: Raymond
authors.initials: R
authors.lastname: Comenzo
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.forename: Janeen
authors.initials: J
authors.lastname: Azare
authors.forename: William
authors.initials: W
authors.lastname: Bornmann
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Bromberg
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000166:cytology / Q000187:drug effects; D018920:Coculture Techniques; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D006825:Hybridomas / Q000187:drug effects / Q000473:pathology; D015850:Interleukin-6 / Q000494:pharmacology; D053612:Janus Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D009101:Multiple Myeloma / Q000473:pathology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011728:Pyridones / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D017154:Stromal Cells / Q000502:physiology; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: C524063:2-tert-butyl-9-fluoro-3,6-dihydro-7H-benz(h)imidazo(4,5-f)isoquinoline-7-one; D001562:Benzimidazoles; D015850:Interleukin-6; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D053612:Janus Kinases; D048049:Extracellular Signal-Regulated MAP Kinases