DCLK1-Targeting PROTAC as a Therapeutic Strategy for Acute Lung Injury: Inhibition of Pro-inflammatory Macrophage Polarization

Abstract Doublecortin-like kinase 1 (DCLK1) has emerged as a promising therapeutic target in acute inflammatory diseases. Despite DCLK1’s emerging role in acute lung injury (ALI), conventional occupancy-driven inhibitors face limitations in efficacy and potential toxicity. Herein, we designed and synthesized the first series of DCLK1-targeting proteolysis-targeting chimeras (PROTACs). Among them, compound D11 potently degraded DCLK1 via the ubiquitin-proteasome system, with DC50 values of 36.93 nM and 75.67 nM in RAW264.7 and THP-1 cells, respectively. D11 effectively suppressed lipopolysaccharide (LPS)-induced macrophage M1 polarization in vitro and reduced pro-inflammatory cytokine production. In LPS-induced acute lung injury (ALI) model, D11 administration significantly attenuated lung pathology, decreased inflammatory cell infiltration, lowered cytokine levels, and inhibited pulmonary M1 macrophage polarization with no detectable toxicity. These findings demonstrate that targeted degradation of DCLK1 via PROTAC represents a viable and effective strategy for treating ALI, highlighting D11 as a promising lead compound for further development.