APH02174 hemiformic

APH02174 hemiformic is a highly selective and orally active IRAK4 PROTAC degrader with the DC₅₀ of 4.01 nM in THP-1 cells. APH02174 hemiformic blocks inflammatory signals by inhibiting IL-6 release. APH02174 hemiformic can be used for research on inflammatory conditions such as psoriasis vulgaris and rheumatoid arthritis ^[1]. (Pink: IRAK4 ligand; Blue: Cereblon ligand; Black: linker).

In Vivo, APH02174 (10-100 mg/kg; p.o.; twice daily; for 7 days) hemiformic reduces imiquimod-induced psoriasis-like skin inflammation significantly degrades the IRAK4 protein level in the spleen of the Imiquimod (IMQ) induced mice^[1]. APH02174 (30-100 mg/kg; p.o.; once daily; for 14 days) hemiformic significantly improves arthritis in the rheumatoid arthritis mice^[1].

In Vitro, APH02174 (0.24-1000 nM) hemiformic can selectively degrade IRAK4 protein in various cells, including THP-1 (DC₅₀ = 4.01 nM), hPBMCs (DC₅₀ = 0.43 nM) and mouse PBMCs (DC₅₀ = 3.57 nM) ^[1]. APH02174 (0.03-2000 nM; 24 h) hemiformic significantly inhibits the Lipopolysaccharides (LPS) induced IL-6 release in the hPBMCs (IC₅₀ = 16.43 nM) ^[1].

References:
[1]. Wu XW, et al. Discovery of APH02174 as a Highly Selective and Orally Bioavailable IRAK4 Degrader for the Treatment of Inflammatory Diseases. J Med Chem. 2025 Jun 26;68(12):12845-12861.