FIP22 is a potent and selective IRAK4 PROTAC degrader with a DC50 of 3.2 nM in HEK293T cells and 10.6 nM in THP-1 cells. It induces the ubiquitin-proteasome system through the formation of an IRAK4-FIP22-CRBN ternary complex (EC50= 12.63 nM), effectively inhibiting the NF-κB and MAPK signaling pathways mediated by IRAK4. FIP22 is applicable for researching atopic dermatitis.

IRAK4:3.2 nM (DC50)

FIP22, at concentrations ranging from 0.02 to 10 μM over 0 to 48 hours, induces rapid and sustained degradation of IRAK4 protein in HEK293T cells, without affecting CRBN substrates or other IRAK isoforms. In THP-1 cells, FIP22 (0.02-2 μM) inhibits phosphorylation of key proteins in the LPS-induced NF-κB and MAPK signaling pathways and reduces the secretion of pro-inflammatory cytokines IL-6, TNF-α, and chemokine CXCL8. At 120 μM, FIP22 does not cause cytotoxicity in four normal cell lines (HEK293T, H2C9, BRL-3A, LO2).

FIP22 (administered at 10-30 mg/kg via intraperitoneal injection, once daily for 25 days) demonstrated a notable therapeutic effect in a mouse model of atopic dermatitis induced by 2,4-dinitrochlorobenzene (DNCB).