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High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
Published on: November 9, 2020
Development of APH003─a Highly Potent, Selective, and Orally Bioavailable IRAK4 PROTAC Degrader for the Treatment of
Xi-Wei Wu1,2, Zhao-Min Chen2, Cui Gao2
1School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
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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