Discovery of a Novel Dual-Target Inhibitor of ERK1 and ERK5 That Induces Regulated Cell Death to Overcome Compensatory Mechanism in Specific Tumor Types

ERK1
and ERK5 are proposed to have pivotal roles in several types
of cancer. Under some circumstance, ERK5 may provide a common bypass
route, which rescues proliferation upon abrogation of ERK1 signaling.
Thus, we accurately classified the tumor types from The Cancer Genome
Atlas (TCGA) based on the expression levels of ERK1 and ERK5. We proposed
a novel therapeutic strategy to overcome the above-mentioned compensatory
mechanism in specific tumor types by co-targeting both ERK1 and ERK5.
On the basis of the idea of overcoming ERK5 compensation mechanism, 22ac (ADTL-EI1712) as the first selective dual-target inhibitor
of ERK1 and ERK5 was discovered to have potent antitumor effects in vitro and in vivo. Interestingly, this
compound was found to induce regulated cell death accompanied by autophagy
in MKN-74 cells. Taken together, our results warrant the potential
of this dual-target inhibitor as a new candidate drug that conquers
compensatory mechanism in certain tumor types.