Development of APH003─a Highly Potent, Selective, and Orally Bioavailable IRAK4 PROTAC Degrader for the Treatment of Inflammatory Diseases

  • J Med Chem. 2026 Jul 9;69(13):15685-15701. doi: 10.1021/acs.jmedchem.6c00828.
Xi-Wei Wu  1  2 ,  Zhao-Min Chen  2 ,  Cui Gao  2 ,  Mi Tian  2 ,  Xi-Le Liu  2 ,  Hui Wang  2 ,  Hai-Jie Chen  2 ,  Han-Xiong Li  2 ,  Wen-Qian Yang  2 ,  Lin-Kun An  1  3  4
Affiliations
  • 1. School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
  • 2. ApicHope Pharmaceutical Group Co, Ltd., Guangzhou 510000, China.
  • 3. State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
  • 4. Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangzhou 510006, China.
PMID: 42363007 DOI: 10.1021/acs.jmedchem.6c00828
Abstract

Interleukin-1 receptor-associated kinase 4 (IRAK4) represents an attractive therapeutic target in inflammatory and oncological indications due to its pivotal role as a signaling mediator downstream of TLR and IL-1R. We previously reported a series of spirocyclic IRAK4 degraders and identified APH02174 as a selective, orally bioavailable degrader. However, its hERG inhibition, hepatocyte stability, and variable cross-species PK inspired further structural optimization. The optimization gave eight PROTACs (5-10, 14, and APH003) which exhibited high IRAK4 degradation ability (DC50 ≤ 2 nM, DC90 ≤ 10 nM, and Dmax ≥ 85%) in vitro. APH003 exhibited favorable PK parameters, low hERG inhibition, improved hepatocyte stability, and pronounced anti-inflammatory efficacy in animal models. Dose range-finding studies in rat and dog models supported its safety profile. Based on these improvements in safety, cross-species PK, efficacy, and preliminary toxicology, APH003 was selected as a preclinical candidate for GLP toxicological studies.

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