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

Ralimetinib, a small-molecule drug developed as an inhibitor of the p38α mitogen-activated protein kinase, has progressed to Phase 2 clinical trials in oncology. In this study, we show that ralimetinib shares similarities with EGFR-targeting drugs based on pharmacogenomic profiling. We found that ralimetinib inhibits EGFR kinase activity both in vitro and in cellulo. Interestingly, the sensitivity to ralimetinib remains unchanged even with the deletion of the p38α and p38β genes, but its effects are blocked by the presence of the EGFR-T790M gatekeeper mutation.

Additionally, we solved the cocrystal structure of ralimetinib bound to EGFR, further confirming that the drug acts as an ATP-competitive inhibitor of EGFR. Although ralimetinib is over 30 times less potent against EGFR compared to p38α, its inhibition of EGFR appears to be the primary driver of its anticancer effects. These findings challenge the notion of p38α as a valuable anticancer target and suggest a multi-modal approach for elucidating a drug’s LY2228820 mechanism of action.