Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes.
Nearly 50% of human malignancies exhibit unregulated RAS-ERK signaling; inhibiting it is a valid strategy for antineoplastic intervention. Upon activation, ERK dimerize, which is essential for ERK extranuclear, but not for nuclear, signaling. Here, we describe a small molecule inhibitor for ERK dimerization that, without affecting ERK phosphorylation, forestalls tumorigenesis driven by RAS-ERK pathway oncogenes. This compound is unaffected by resistance mechanisms that hamper classical RAS-ERK pathway inhibitors. Thus, ERK dimerization inhibitors provide the proof of principle for two understudied concepts in cancer therapy: (1) the blockade of sub-localization-specific sub-signals, rather than total signals, as a means of impeding oncogenic RAS-ERK signaling and (2) targeting regulatory protein-protein interactions, rather than catalytic activities, as an approach for producing effective antitumor agents.
Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Cantabria, Santander 39011, Spain.
Ana
A
Herrero
Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Cantabria, Santander 39011, Spain.
Adán
A
Pinto
Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Cantabria, Santander 39011, Spain.
Paula
P
Colón-Bolea
Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Cantabria, Santander 39011, Spain.
Berta
B
Casar
Faculty of Life Sciences, University of Manchester, Manchester M13 9PL, UK.
Mary
M
Jones
Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Cantabria, Santander 39011, Spain.
Lorena
L
Agudo-Ibáñez
Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Cantabria, Santander 39011, Spain; Departamento de Fisiología y Farmacología, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III Universidad de Cantabria, Santander 39011, Spain.
Rebeca
R
Vidal
Stem Cells and Cancer Laboratory, Translational Research Program, Vall d'Hebron Institute of Oncology (VHIO), Barcelona 08035, Spain.
Stephan P
SP
Tenbaum
Stem Cells and Cancer Laboratory, Translational Research Program, Vall d'Hebron Institute of Oncology (VHIO), Barcelona 08035, Spain.
Paolo
P
Nuciforo
Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Cantabria, Santander 39011, Spain; Departamento de Fisiología y Farmacología, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III Universidad de Cantabria, Santander 39011, Spain.
Elsa M
EM
Valdizán
Vichem Chemie Research Ltd., 1022 Budapest, Hungary.
Zoltan
Z
Horvath
Vichem Chemie Research Ltd., 1022 Budapest, Hungary; Department of Pharmaceutical Chemistry, Semmelweis University, 1092 Budapest, Hungary.
Laszlo
L
Orfi
Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain.
Antonio
A
Pineda-Lucena
Pharmacognosy Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, 1200 Bruxelles, Belgium.
Emilie
E
Bony
Vichem Chemie Research Ltd., 1022 Budapest, Hungary; MTA-SE Pathobiochemistry Research Group, Department of Medical Chemistry, Semmelweis University, 1092 Budapest, Hungary.
Gyorgy
G
Keri
Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain.
Germán
G
Rivas
Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Cantabria, Santander 39011, Spain; Departamento de Fisiología y Farmacología, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III Universidad de Cantabria, Santander 39011, Spain.
Angel
A
Pazos
ProtoQSAR S.L., 46008 Valencia, Spain.
Rafael
R
Gozalbes
Stem Cells and Cancer Laboratory, Translational Research Program, Vall d'Hebron Institute of Oncology (VHIO), Barcelona 08035, Spain.
Héctor G
HG
Palmer
Departamento de Fisiología y Farmacología, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III Universidad de Cantabria, Santander 39011, Spain.
Adam
A
Hurlstone
Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Cantabria, Santander 39011, Spain. Electronic address: crespop@unican.es.
Piero
P
Crespo
D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D055503:Protein Multimerization / Q000187:drug effects*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D015027:Zebrafish; D018631:ras Proteins / Q000378:metabolism*
C000602901:DEL-22379; D007211:Indoles; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D018631:ras Proteins