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 KPT9274 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 CPS-021, a selective PAK4 degrader derived from our previously reported compound CPL-042 conjugated to pomalidomide. CPS-021 induced selective degradation of PAK4 with DC50 = 50 nM and exhibited significant antimigratory and invasive activity. The A549-luc lung metastasis in vivo model demonstrated that CPS-021 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 CPS-021 as a valuable tool compound for conducting in-depth biological investigations of group II PAKs.