Design, Synthesis, and Biological Evaluation of Selective PAK4 Degrader for the Treatment of Lung Tumor Metastasis

PAK4, the most studied member of group II PAK, plays crucial roles in multiple cancer cell signaling pathways. To date , only PAK4 inhibitor <b>KPT9274</b> is under clinical development with no detailed binding mechanism. The PROTAC technology offers a new chance to study PAK4 by selective protein degradation. Here, we report the development of <b>CPS-021</b>, a selective PAK4 degrader derived from our previously reported compound <b>CPL-042</b> conjugated to pomalidomide. <b>CPS-021</b> induced selective degradation of PAK4 with DC₅₀ = 50 nM and exhibited significant antimigratory and invasive activity. The A549-luc lung metastasis <i>in vivo</i> model demonstrated that <b>CPS-021</b> effectively inhibited the invasion and metastasis of tumor cells in nude mice. Our findings provide evidence that the selective PAK4 degrader exhibits significant pharmacological effects in suppressing cancer cell migration and invasion. These results support the further development of <b>CPS-021</b> as a valuable tool compound for conducting in-depth biological investigations of group II PAKs.