First DCLK1 PROTACs curb macrophage inflammation in acute lung injury
- Replaces occupancy-based inhibition of the kinase DCLK1 with induced degradation, reporting the first PROTAC series against this target.
- Lead degrader D11 removes DCLK1 through the ubiquitin-proteasome pathway in both mouse and human macrophage-like cell lines.
- In cells it blunts LPS-driven M1 polarization and cytokine release; in an LPS lung injury model it eases tissue damage, immune cell influx and M1 skewing without evident toxicity.
💡 Points Based on the abstract
Is the benefit really from losing DCLK1, or from degrader off-targets? DCLK1 inhibitors are known to be promiscuous kinase binders, and a PROTAC inherits that warhead's polypharmacology. I'd want an inactive-epimer E3 ligand control, a warhead-only comparator, and proteomics. Also worth asking: DCLK1 has a kinase and a doublecortin domain, so degradation may remove scaffolding roles that inhibitors never touch.