2020 AACR: Different pharmacodynamic profiles of ERK1/2 inhibition can elicit comparable anti-tumor activity

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Different pharmacodynamic profiles of ERK1/2 inhibition can elicit comparable anti-tumor activity

Summary

  • The mitogen activated protein kinase (MAPK) pathway is frequently dysregulated in cancer, leading to activation of the downstream kinases ERK1/2 (ERK). Phosphorylation of ERK substrates such as p90RSK (RSK) leads to cancer cell proliferation.
  • Clinical efficacy can be limited by toxicity, so it is important to establish an optimal, tolerated dose schedule which maximises efficacy. Preclinical studies investigating the duration of target engagement required for efficacy can inform on dose schedules to be tested in the clinic.
  • A number of compounds under clinical development target ERK activity directly: we have recently described the development of a novel, potent and selective small molecule inhibitor of ERK, the lead compound, using fragment-based drug discovery1.