The CDK9-targeting degrader PO-8 alleviates LPS-induced inflammation by inhibiting JAK-STAT signaling in vitro and in vivo

Cyclin-dependent kinase 9 (CDK9) emerges as a crucial activator of inflammatory responses, but the therapeutic potential of CDK9 degraders in inflammation remains largely unexplored. In this study, we demonstrated that iCDK9, a selective CDK9 inhibitor, effectively suppressed lipopolysaccharide (LPS)-induced inflammation in RAW 264.7 macrophages. Leveraging proteolysis-targeting chimera (PROTAC) technology, we designed and synthesized twelve iCDK9-based PROTAC molecules. Among them, PO-8 was identified as an excellent CDK9 degrader with potent anti-inflammatory activity. Moreover, PO-8 selectively induced CDK9 degradation via the ubiquitin–proteasome system, resulting in a significant attenuation of LPS-triggered inflammatory responses both in vitro and in vivo. Notably, PO-8 exhibited an improved safety profile and a wider therapeutic window compared to its parent inhibitor, iCDK9. Mechanistic studies revealed that PO-8-mediated CDK9 degradation disrupts the JAK2-STAT3 signaling pathway, thereby mitigating inflammation. To the best of our knowledge, this study is the first to establish the anti-inflammatory efficacy of a small-molecule CDK9 degrader, highlighting PROTAC-based CDK9 targeting as a promising therapeutic strategy for inflammatory diseases.