Synthesis and anticancer activity of parthenolide-based PROTACs for IKKβ degradation
- Bioorg Med Chem Lett. 2026 Jun:135:130571. doi: 10.1016/j.bmcl.2026.130571.
- 1. School of Pharmacy and Food Engineering, Wuyi University, Jiangmen 529020, China.
- 2. Guangzhou Henovcom Bioscience Co., Ltd, Guangzhou, 510530, China.
- 3. School of Pharmacy and Food Engineering, Wuyi University, Jiangmen 529020, China.. Electronic address: [email protected].
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.