2. Academic Validation
  3. Discovery of GSI526: a potent IRAK4-targeting PROTAC degrader with efficient degradation and suppression of inflammatory signaling

Discovery of GSI526: a potent IRAK4-targeting PROTAC degrader with efficient degradation and suppression of inflammatory signaling

  • Bioorg Med Chem Lett. 2026 Sep:138:130680. doi: 10.1016/j.bmcl.2026.130680.
Bingjie Yin 1,  Zhishuo Gao 1,  Yan Ma 1,  Zhuoyue Li 2,  Mengjun Ma 3
Affiliations

Affiliations

  • 1 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong 266003, China.
  • 2 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong 266003, China; Center for Targeted Protein Degradation and Drug Discovery, Ocean University of China, Qingdao, Shandong 266003, China. Electronic address: [email protected].
  • 3 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong 266003, China; Center for Targeted Protein Degradation and Drug Discovery, Ocean University of China, Qingdao, Shandong 266003, China. Electronic address: [email protected].
PMID: 42097519 DOI: 10.1016/j.bmcl.2026.130680
Abstract

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a promising therapeutic target for inflammatory diseases. However, inhibition of its kinase activity alone often results in incomplete blockade of inflammatory signaling and limited therapeutic efficacy. To address this limitation, we designed and synthesized a novel proteolysis-targeting chimera (PROTAC) aimed at degrading IRAK4. Among the synthesized compounds, GSI526 emerged as a potent degrader, demonstrating efficient IRAK4 degradation in THP-1 cells with a DC₅₀ of 40.17 nM. Mechanistic studies confirmed that GSI526 acts via the ubiquitin-proteasome system, effectively suppressing the IRAK4-mediated NF-κB and MAPK signaling pathways. Furthermore, GSI526 exhibited a favorable preliminary safety profile. Collectively, these findings identify GSI526 as a promising IRAK4-targeting degrader, offering an alternative therapeutic strategy and a candidate for further drug development.

Keywords

Degrader; IRAK4; MAPK; NF-κB; PROTAC.

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