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Small molecule ERK5 kinase inhibitors paradoxically activate ERK5 signalling: be careful what you wish for…

Simon J Cook1, Julie A Tucker2, Pamela A Lochhead1

  • 1Signalling Laboratory, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, U.K.

Biochemical Society Transactions
|September 11, 2020
PubMed

Insights

Small molecule ERK5 kinase inhibitors (ERK5i) can paradoxically activate ERK5's transactivation domain, leading to unintended physiological effects. This review covers assays, challenges, and mechanisms of paradoxical kinase activation.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • ERK5 is a protein kinase with therapeutic potential in cancer and inflammation.
  • ERK5 kinase inhibitors (ERK5i) are being developed, but often neglect the ERK5 transactivation domain.
  • ERK5i binding to the kinase domain can paradoxically activate the transactivation domain.

Purpose of the Study:

  • To review assays for monitoring ERK5 kinase and transcriptional activities.
  • To discuss challenges in developing small molecule ERK5 inhibitors.
  • To classify molecular mechanisms of paradoxical protein kinase activation by inhibitors.

Main Methods:

  • Review of existing literature on ERK5 assays and inhibitor development.
  • Classification of paradoxical activation mechanisms based on published data.
  • Analysis of challenges in targeting the ERK5 pathway.

Main Results:

  • ERK5 kinase inhibitors can paradoxically activate the ERK5 transactivation domain.
  • This paradoxical activation can lead to significant physiological consequences.
  • Understanding these mechanisms is crucial for effective drug development.

Conclusions:

  • Mitigating paradoxical activation is essential for safe and effective ERK5 inhibitor therapies.
  • Further research is needed to fully understand and control ERK5 pathway modulation.
  • Development of ERK5i must account for both kinase and transactivation domain activities.
Keywords:
extracellular signal-regulated kinaseskinasesparadoxical activationsmall molecules

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