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

Cell Chem Biol. 2023 Oct 19;30(10):1211-1222.e5. doi: 10.1016/j.chembiol.2023.09.013. Epub 2023 Oct 11.

Abstract

The small-molecule drug ralimetinib was developed as an inhibitor of the p38α mitogen-activated protein kinase, and it has advanced to phase 2 clinical trials in oncology. Here, we demonstrate that ralimetinib resembles EGFR-targeting drugs in pharmacogenomic profiling experiments and that ralimetinib inhibits EGFR kinase activity in vitro and in cellulo. While ralimetinib sensitivity is unaffected by deletion of the genes encoding p38α and p38β, its effects are blocked by expression of the EGFR-T790M gatekeeper mutation. Finally, we solved the cocrystal structure of ralimetinib bound to EGFR, providing further evidence that this drug functions as an ATP-competitive EGFR inhibitor. We conclude that, though ralimetinib is >30-fold less potent against EGFR compared to p38α, its ability to inhibit EGFR drives its primary anticancer effects. Our results call into question the value of p38α as an anticancer target, and we describe a multi-modal approach that can be used to uncover a drug's mechanism-of-action.

Keywords: EGFR; cancer; drug targeting; mechanism of action; pharmacogenomics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ErbB Receptors
  • Humans
  • Lung Neoplasms*
  • Mitogen-Activated Protein Kinase 14* / genetics
  • Mitogen-Activated Protein Kinase 14* / metabolism
  • Mutation
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology

Substances

  • ErbB Receptors
  • Protein Kinase Inhibitors
  • Mitogen-Activated Protein Kinase 14