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.
