APH02174

APH02174 : Degrader (PROTAC) of IRAK4

Structure

SERP Rating

In Cells

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In Model Organisms

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Probe APH02174 is in the process of SERP review.

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Information

IRAK4

Degrader (PROTAC)

up to 100 nM

In Vitro Validations

No in Vitro Validations

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency assay, off target (cells): The degradative selectivity of APH02174 was evaluated using tandem mass tag-based global discovery proteomics. After being treated with 300 nM APH02174 for 24 h, IRAK4 was the most degraded protein (>200-fold than other proteins, among approximately 8000 total proteins) in hPBMCs.

Potency assay, off target (cells): To determine whether APH02174 can degrade the transcription factor SALL4 and Zn-finger proteins (IKZF1, IKZF3), WB assays in hPBMCs were conducted, and the degradation of these targets was not observed at the highest testing concentration, 1 μM.

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SERP ratings and comments

SERP+ Ratings

In Cell Rating

In Model Organisms

SERP+ Comments:

This is a potent degrader of IRAK4 as determined by HiBiT-IRAK4 assays in THP1cells, as well as by Western blot in human and mouse PBMCs. Degradation selectivity characterised by global proteomics showed IRAK4 degradation with >200 fold selectivity over other proteins. It is worth noting that other proteins were significantly degraded, but the identity of these proteins was not disclosed. The IRAK4 warhead inhibitor selectivity is not reported and therefore off target kinase inhibition cannot cannot be entirely ruled out as a potential influence on an observed phenotype. There is no inactive control used and no competition experiments with bivalent binders have been carried out to conclusively prove target engagement. However, global proteomics are supportive of a specific IRAK4 engagement. The PROTAC has been comprehensively profiled in vivo, with a dose-exposure-degradation relationship defined in the psoriasis model in mice (>80% depletion of IRAK4 in splenic tissue for 30m/kg and 100mg/kg cohorts).

(last updated: 6 Feb 2026 )