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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
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Characterization of p38α autophosphorylation inhibitors that target the non-canonical activation pathway

Lorena González1, Lucía Díaz2, Joan Pous1

  • 1Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028, Barcelona, Spain.

Nature Communications
|June 12, 2023
PubMed

Insights

New non-canonical p38α inhibitors (NC-p38i) were identified to target specific functions of the p38α pathway. These compounds offer a novel therapeutic strategy by selectively modulating p38α signaling in diseases.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • p38α kinase is crucial for cellular stress responses.
  • Dysregulation of p38α signaling is implicated in inflammation, immune disorders, and cancer.
  • Previous p38α inhibitors showed limited clinical success, necessitating alternative approaches.

Purpose of the Study:

  • To identify novel compounds targeting p38α signaling.
  • To explore alternative mechanisms for p38α modulation.
  • To develop targeted therapies for p38α-related diseases.

Main Methods:

  • In silico identification of non-canonical p38α inhibitors (NC-p38i).
  • Biochemical assays to assess inhibitor activity.
  • Structural analyses to understand inhibition mechanisms.

Main Results:

  • Successfully identified NC-p38i compounds.
  • NC-p38i efficiently inhibit p38α autophosphorylation.
  • NC-p38i show weak inhibition of the canonical p38α pathway activity.

Conclusions:

  • Structural plasticity of p38α can be exploited for therapeutic development.
  • NC-p38i represent a promising strategy for selective p38α pathway modulation.
  • Targeting specific p38α functions offers new therapeutic opportunities for various diseases.

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