Extracellular signal-regulated kinases 1, 2, 5 (ERK1/2/5) belong to the mitogen-activated protein kinase (MAPK) family and participate in a variety of biological processes. Up to now, the activation of the ERKs signaling cascade has been confirmed in more than 80% of tumors. Recent studies have shown that ERK5 can provide a compensation pathway after the failure of ERK1/2 signal transduction, thereby saving the proliferation of tumor cells. The compensation mechanism may be one of the important reasons for the inefficacy in clinical trials of existing ERK1/2 and ERK5 inhibitors, and there is no application of dual-targeted inhibitor or combination therapy. To solve this problem, we first accurately classified the tumor types in The Cancer Genome Atlas (TCGA) based on the expression levels of ERK1/2 and ERK5. Subsequently, a dual-target design was carried out according to the ATP-competitive hinge regions with high similarity in their sequences and structures, and a series of candidate compounds were synthesized based on the space-oriented optimization design strategy. After multiple rounds of activity screening, the first inhibitor ADTL-EI1712 that targets the compensation mechanism of ERK1/2/5 was obtained. Targeting studies have shown that ADTL-EI1712 shows good targeting specificity in KINOMEscan screening and siRNA interference experiments. <i>In vivo</i> and<i> in vitro</i> anti-tumor effect and mechanism studies have shown that in tumors with high expression of ERK1/2/5, and high expression of ERK1/2 or ERK5, ADTL-EI1712 can exert a good anti-proliferative effect with no obvious toxic effects. In the pharmacokinetic study, ADTL-EI1712 showed moderate pharmacokinetic characteristics, demonstrating that ADTL-EI1712 can be used as a suitable oral candidate compound. Taken together, our results warrant the potential of this multi-target inhibitor as a new candidate drug that conquers compensatory mechanism in certain tumor types (Figure 1).

Design and synthesis of multi-targeted ERK1/2/5 inhibitors to overcome compensatory mechanism based on precise tumor classification

ACS Spring Meeting 2021

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