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Inhibition of a lower potency target drives the anticancer activity of a clinical p38 inhibitor

Debanjan Bhattacharjee1, Jaweria Bakar1, Surbhi P Chitnis2

  • 1Yale University School of Medicine, New Haven, CT 06511, USA.

Cell Chemical Biology
|October 12, 2023
PubMed

Insights

Ralimetinib, developed as a p38α kinase inhibitor, surprisingly targets the epidermal growth factor receptor (EGFR). Its anticancer effects stem from EGFR inhibition, not p38α, questioning p38α

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Ralimetinib is a small-molecule drug developed as a p38α mitogen-activated protein kinase inhibitor.
  • The drug has progressed to phase 2 clinical trials for cancer treatment.

Purpose of the Study:

  • To investigate the unexpected pharmacogenomic profile of ralimetinib.
  • To determine the primary molecular target responsible for ralimetinib's anticancer activity.
  • To elucidate the mechanism of action of ralimetinib.

Main Methods:

  • Pharmacogenomic profiling experiments.
  • In vitro and cellular kinase inhibition assays.
  • Genetic manipulation (gene deletion and mutation expression).
  • Cocrystal structure determination of ralimetinib bound to EGFR.

Main Results:

  • Ralimetinib exhibits pharmacogenomic similarities to EGFR inhibitors.
  • Ralimetinib directly inhibits EGFR kinase activity in vitro and in cells.
  • Ralimetinib's effects are independent of p38α/β but are blocked by the EGFR-T790M mutation.
  • The cocrystal structure confirms ralimetinib as an ATP-competitive EGFR inhibitor.

Conclusions:

  • Ralimetinib's primary anticancer effects are driven by EGFR inhibition, despite lower potency compared to p38α inhibition.
  • The study questions the therapeutic value of p38α as an anticancer target.
  • A multimodal approach is presented for uncovering drug mechanisms of action.
Keywords:
EGFRcancerdrug targetingmechanism of actionpharmacogenomics

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