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

The small-molecule drug ralimetinib was developed as an inhibitor of the p38a 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 p38a and p38b, 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 p38a, its ability to inhibit EGFR drives its primary anticancer effects. Our results call into question the value of p38a as an anticancer target, and we describe a multi-modal approach that can be used to uncover a drug's mechanism-of-action.

Automated summary

This study demonstrates that Ralimetinib inhibits EGFR kinase activity and drives its primary anticancer effects. The findings question the value of p38a as an anticancer target and propose a multi-modal approach to uncovering a drug's mechanism-of-action.