Discovery of Rigid Linker-Based IRAK4 PROTACs with Improved Metabolic Stability for the Treatment of Inflammatory Diseases

  • J Med Chem. 2025 Aug 28;68(16):17874-17896. doi: 10.1021/acs.jmedchem.5c01620.
Yapeng Fan  1 ,  Rongxiang Ma  1 ,  Kabonde Makasa Njobvu  1 ,  Yifan Wang  1 ,  Yichang Ren  2 ,  Renquan Fu  1 ,  Chenyu Zhang  3 ,  Feifei Liu  1 ,  Zhongping Jiang  1 ,  Yong Rao  1 ,  Congjun Xu  1 ,  Ling Huang  1 ,  Jianjun Chen  2 ,  Jin Liu  1
Affiliations
  • 1. Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
  • 2. School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China.
  • 3. State Key Laboratory of Respiratory Disease, Guangzhou Key Laboratory of Tuberculosis Research, Department of Pharmacy, Guangzhou Chest Hospital, Institute of Tuberculosis, Guangzhou Medical University, Guangzhou 510095, China.
PMID: 40814267 DOI: 10.1021/acs.jmedchem.5c01620
Abstract

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a promising therapeutic target for inflammatory diseases. However, solely inhibiting IRAK4 kinase activity fails to fully block inflammatory signaling, resulting in limited efficacy. Herein, we describe the design and synthesis of novel IRAK4 degraders based on a proteolysis-targeting chimera (PROTAC) strategy. The preferred compound, FIP22, effectively degraded cellular IRAK4 with a DC50 of 3.2 nM, 115-fold higher than the lead compound DE5. Mechanistically, FIP22 induces the ubiquitin-proteasome system by forming an IRAK4-FIP22-CRBN ternary complex, thereby potently blocking IRAK4-mediated NF-κB and MAPK signaling pathways. Concurrently, FIP22 demonstrated favorable safety profiles and excellent metabolic stability (e.g., 180-fold longer half-life than the lead compound DE5). Furthermore, FIP22 exhibited significant therapeutic efficacy in a 2,4-dinitrochlorobenzene-induced atopic dermatitis mouse model. In summary, FIP22 represents a candidate IRAK4 Degrader for alternative targeting strategies and advanced drug development.

Products