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

Authors

Xi-Wei Wu, Zhao-Min Chen, Cui Gao, Mi Tian, Xi-Le Liu, Hui Wang, Hai-Jie Chen, Han-Xiong Li, Wen-Qian Yang, Lin-Kun An

Published in

Journal of medicinal chemistry. Jun 26, 2026. Epub Jun 26, 2026.

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 D_max ≥ 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.

PMID:
42363007
Bibliographic data and abstract were imported from PubMed on 27 Jun 2026.

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