Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes PMID: 26267534

ADC Targets in Oncology

2026-04-10

Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes

Cancer Cell. 2015 Aug 10;28(2):170-82. doi: 10.1016/j.ccell.2015.07.001.

Ana Herrero ¹ , Adán Pinto ¹ , Paula Colón-Bolea ¹ , Berta Casar ¹ , Mary Jones ² , Lorena Agudo-Ibáñez ¹ , Rebeca Vidal ³ , Stephan P Tenbaum ⁴ , Paolo Nuciforo ⁴ , Elsa M Valdizán ³ , Zoltan Horvath ⁵ , Laszlo Orfi ⁶ , Antonio Pineda-Lucena ⁷ , Emilie Bony ⁸ , Gyorgy Keri ⁹ , Germán Rivas ¹⁰ , Angel Pazos ³ , Rafael Gozalbes ¹¹ , Héctor G Palmer ⁴ , Adam Hurlstone ¹² , Piero Crespo ¹³

Affiliations

1. Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Cantabria, Santander 39011, Spain.
2. Faculty of Life Sciences, University of Manchester, Manchester M13 9PL, UK.
3. 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.
4. Stem Cells and Cancer Laboratory, Translational Research Program, Vall d'Hebron Institute of Oncology (VHIO), Barcelona 08035, Spain.
5. Vichem Chemie Research Ltd., 1022 Budapest, Hungary.
6. Vichem Chemie Research Ltd., 1022 Budapest, Hungary; Department of Pharmaceutical Chemistry, Semmelweis University, 1092 Budapest, Hungary.
7. Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain.
8. Pharmacognosy Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, 1200 Bruxelles, Belgium.
9. Vichem Chemie Research Ltd., 1022 Budapest, Hungary; MTA-SE Pathobiochemistry Research Group, Department of Medical Chemistry, Semmelweis University, 1092 Budapest, Hungary.
10. Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain.
11. ProtoQSAR S.L., 46008 Valencia, Spain.
12. 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.
13. Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Cantabria, Santander 39011, Spain. Electronic address: [email protected].

Abstract

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.