title: Potent antimyeloma activity of a novel ERK5/CDK inhibitor.
abstract: OBJECTIVE
  To analyze the antimyeloma potential of TG02, an ERK5/CDK inhibitory drug.
  
  
  METHODS
  Utilizing different multiple myeloma cell lines we determined the effect of TG02 over viability by MTT assays. The apoptotic effect over multiple myeloma patient samples was studied ex vivo by cytometry. The mechanism of action of TG02 was analyzed in the cell line MM1S, studying its effect on the cell cycle, the induction of apoptosis, and the loss of mitochondrial membrane potential by cytometry and Western blot. Two models of multiple myeloma xenograft were utilized to study the in vivo action of TG02.
  
  
  RESULTS
  TG02 potently inhibited proliferation and survival of multiple myeloma cell lines, even under protective bone marrow niche conditions, and selectively induced apoptosis of primary patient-derived malignant plasma cells. TG02 displayed significant single-agent activity in two multiple myeloma xenograft models, and enhanced the in vivo activity of bortezomib and lenalidomide. Signaling analyses revealed that the drug simultaneously blocked the activity of CDKs 1, 2, and 9 as well as the MAP kinase ERK5 in MM1S cells, leading to cell-cycle arrest and rapid commitment to apoptosis. TG02 induced robust activation of both the intrinsic and extrinsic pathways of apoptosis, and depletion of XIAP and the key multiple myeloma survival protein Mcl-1.
  
  
  CONCLUSIONS
  TG02 is a promising new antimyeloma agent that is currently in phase I clinical trials in leukemia and multiple myeloma patients.
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer, CSIC-IBSAL-Universidad de Salamanca, Spain.
authors.forename: Stela
authors.initials: S
authors.lastname: Álvarez-Fernández
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Ortiz-Ruiz
authors.forename: Tracy
authors.initials: T
authors.lastname: Parrott
authors.forename: Sara
authors.initials: S
authors.lastname: Zaknoen
authors.forename: Enrique M
authors.initials: EM
authors.lastname: Ocio
authors.forename: Jesús
authors.initials: J
authors.lastname: San Miguel
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Burrows
authors.forename: Azucena
authors.initials: A
authors.lastname: Esparís-Ogando
authors.forename: Atanasio
authors.initials: A
authors.lastname: Pandiella
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D000077269:Lenalidomide; D016513:Mice, SCID; D048054:Mitogen-Activated Protein Kinase 7 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009101:Multiple Myeloma / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000095043:Cyclin-Dependent Kinase-Activating Kinase
chemical_list: C570909:14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene; D001897:Boronic Acids; D006576:Heterocyclic Compounds, 4 or More Rings; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D013792:Thalidomide; D000069286:Bortezomib; D016203:CDC2 Protein Kinase; C495894:CDK2 protein, human; C467969:CDK9 protein, human; D051357:Cyclin-Dependent Kinase 2; D042863:Cyclin-Dependent Kinase 9; D018844:Cyclin-Dependent Kinases; D048054:Mitogen-Activated Protein Kinase 7; D000077269:Lenalidomide; D000095043:Cyclin-Dependent Kinase-Activating Kinase