Synthesis and anticancer activity of parthenolide-based PROTACs for IKKβ degradation.

Parthenolide is a natural IκB kinase β (IKKβ) inhibitor. Converting it into a PROTAC (proteolysis-targeting chimeras) may lead to improved pharmacological efficacy. Herein, we report the design, synthesis, and biological evaluation of a novel series of parthenolide-based PROTACs. Among them, compound 8 exhibited potent anti-proliferative activity, especially against triple-negative breast cancer MDA-MB-231 cells. Mechanistic studies revealed that 8 acts as an effective IKKβ degrader, inducing degradation via the ubiquitin-proteasome system (DC50 = 7.15 μM, 91.24% degradation at 10 μM). Furthermore, treatment with 8 was associated with significant apoptosis and G1-phase cell cycle arrest in MDA-MB-231 cells. This work provides initial evidence that the parthenolide scaffold can be leveraged for targeted protein degradation, supporting the future development of IKKβ-directed degraders.