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Updated: Sep 21, 2025

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Development of small molecule extracellular signal-regulated kinases (ERKs) inhibitors for cancer therapy

Xiaoli Pan1, Junping Pei1, Aoxue Wang1

  • 1State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China.

Acta Pharmaceutica Sinica. B
|June 1, 2022
PubMed

Insights

Mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways are crucial in cancer. Targeting ERK1/2 shows promise, but ERK5 can cause resistance, suggesting dual targeting strategies for better cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The MAPK/ERK1/2 pathway is frequently dysregulated in cancer, driving tumor cell proliferation, invasion, and migration.
  • ERK1/2, a distal component, is a promising target for anticancer drugs due to its rare mutations.
  • ERK5 can compensate for ERK1/2 inhibition, potentially leading to drug resistance.

Purpose of the Study:

  • To review the physiological and biological roles of ERK kinases.
  • To analyze structure-activity relationships of small molecule inhibitors targeting ERKs.
  • To discuss therapeutic strategies for overcoming resistance to ERK inhibitors.

Main Methods:

  • Literature review of ERK signaling in cancer.
  • Analysis of structure-activity relationships for ERK inhibitors.
  • Exploration of compensatory mechanisms involving ERK5.

Main Results:

  • ERK1/2 inhibitors are in clinical trials for cancer treatment.
  • ERK5 activation can bypass ERK1/2 inhibition, compromising therapeutic efficacy.
  • Understanding ERK pathway dynamics is key to developing effective anticancer drugs.

Conclusions:

  • Targeting ERK5 or leveraging its compensatory role offers novel oncotherapy strategies.
  • Optimizing ERK inhibitor design and combination therapies can overcome resistance.
  • Further research into ERK structure-activity relationships will guide future drug development.
Keywords:
CancerExtracellular signal-regulated kinase 1/2 inhibitorsExtracellular signal-regulated kinase 5 inhibitorsInhibitionMitogen-activated protein kinasesSelectivity

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