Citation: Zhen Li, Peilu Song, Yujie Liu, Xiuyun Sun, Xin Zhai, Yu Rao. Developing potent anti-inflammatory IRAK4-targeting PROTACs with simplified CRBN ligands[J]. Chinese Chemical Letters, ;2026, 37(3): 111033. doi: 10.1016/j.cclet.2025.111033 shu

Developing potent anti-inflammatory IRAK4-targeting PROTACs with simplified CRBN ligands

Zhen Li ^{a, 1} ,
Peilu Song ^{b, 1} ,
Yujie Liu ^b ,
Xiuyun Sun ^{c, *,} ,
Xin Zhai ^{a, *,} ,
Yu Rao ^{b, c, *,}

a.
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
b.
State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing 100084, China
c.
Changping Laboratory, Beijing 102206, China

sunxiuyun622@126.com

zhaixin_syphu@126.com

yrao@tsinghua.edu.cn

Received Date: 24 October 2024
Revised Date: 28 February 2025
Accepted Date: 4 March 2025
Available Online: 4 March 2025

Figures(5)

Interleukin-1 receptor-associated kinase 4 (IRAK4), a key target with both enzymatic and non-enzymatic functions, plays a pivotal role in autoimmune diseases. Previous studies have demonstrated that proteolysis-targeting chimera (PROTAC) molecules targeting IRAK4 can effectively eliminate both its enzymatic and non-enzymatic functions, showing promising therapeutic potential. However, the development of highly potent, synthetically accessible IRAK4-targeting degraders remains a challenge. In this work, through three rounds of PROTAC library construction, screening, and optimization, we successfully identified a representative compound, LZ-07, which proved to be a highly potent degrader with a half-maximal degradation concentration (DC₅₀) value of 1.14 nmol/L. Notably, compared with KT-474, LZ-07 demonstrated comparable degradation activity and superior inhibition of cytokine production, while featuring a simpler synthetic route with optimized IRAK4 and cereblon (CRBN) ligands. LZ-07-induced degradation of IRAK4 led to marked suppression of key cytokines, including interleukin-6 (IL-6), IL-1β, tumor necrosis factor alpha (TNF-α), and IL-10. This study presents LZ-07 as a novel, highly efficient, and synthetically straightforward IRAK4-targeting degrader, offering a promising tool compound for the study of the potential treatment of autoimmune diseases.
- IRAK4-targeting degraders,
- Simplified CRBN ligands,
- Non-enzymatic functions,
- Inflammatory cytokines inhibition,
- Autoimmune diseases
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