PROteolysis Targeting Chimeras (PROTACs) are bifunctional molecules that degrade target proteins through recruiting E3 ligases. However, their application is limited in part because few E3 ligases can be recruited by known E3 ligase ligands. In this study, we identified piperlongumine (PL), a natural product, as a covalent E3 ligase recruiter, which induces CDK9 degradation when it is conjugated with SNS-032, a CDK9 inhibitor. To evaluate the specificity of the PL-SNS-032 lead conjugate named 955, TMT-based proteomics were conducted to compare 955 with its warhead SNS-032 in MOLT4 cells. As expected, cells exhibited a significant reduction of CDK9 after treatment with 0.1 µM 955 for 1 h and 6 h while treatment with 1 µM SNS-032 for 6 h had no significant effect on CDK9. Interestingly, 955, but not SNS-032, can also potently degrade CDK10.