dIRF4-2 is a selective IRF4 PROTAC degrader with a DC50 value of 2.2 μM. dIRF4-2 forms a ternary complex between IRF4 and CRBN, inducing ubiquitination and proteasomal degradation of IRF4. dIRF4-2 downregulates MYC. dIRF4-2 exhibits anticancer activity against myeloma. dIRF4-2 acts as a chemical probe for investigating IRF4 function, mimicking the IRF4 gene knockout phenotype. dIRF4-2 can be used in the research of multiple myeloma [1]. (Pink: IRF4 ligand; Blue: Cereblon ligand; Black: linker).
In Vitro, dIRF4-2 (1-20 μM; 24 h) induces dose-dependent proteasomal degradation of IRF4 in MM1.S and OPM2 multiple myeloma cell lines, with DC50 values of 2.2 μM and 2.3 μM respectively after 24 h of treatment[1]. dIRF4-2 (2.5 μM; 2-10 h) induces rapid and sustained degradation of IRF4 (initiated within 2 h), and treatment with 2.5 μM for up to 10 h does not affect the off-target novel substrate IKZF3 in MM1.S and OPM2 multiple myeloma cell lines[1]. dIRF4-2 (2.5 μM; 2 h) induces the degradation of IRF4 in MM1.S multiple myeloma cells, and this degradation process is proteasome-dependent; co-treatment with 1 μM bortezomib or 1 μM MG132 followed by a 2-hour incubation restores IRF4 levels[1]. dIRF4-2 (2.5 μM; 4 h) induces highly selective degradation of IRF4 in MM1.S multiple myeloma cells, and exerts no significant effects on other IRF family members or novel CRBN substrates after 4 h of treatment at 2.5 μM[1]. dIRF4-2 (100 μM three-fold dilution series; 96 h, with second dose at 48 h) induces potent, IRF4-dependent cytotoxicity in all tested multiple myeloma cell lines after 96 h of treatment (IC50 0.68-8 μM), while exerting no effect on IRF4-independent HEK293T cells (IC50 > 50 μM)[1].
References:
[1]. Agius MP, et al. Pharmacological targeting of IRF4 as a therapeutic strategy for multiple myeloma. Nat Chem Biol. 2026 May 28.
In Vitro, dIRF4-2 (1-20 μM; 24 h) induces dose-dependent proteasomal degradation of IRF4 in MM1.S and OPM2 multiple myeloma cell lines, with DC50 values of 2.2 μM and 2.3 μM respectively after 24 h of treatment[1]. dIRF4-2 (2.5 μM; 2-10 h) induces rapid and sustained degradation of IRF4 (initiated within 2 h), and treatment with 2.5 μM for up to 10 h does not affect the off-target novel substrate IKZF3 in MM1.S and OPM2 multiple myeloma cell lines[1]. dIRF4-2 (2.5 μM; 2 h) induces the degradation of IRF4 in MM1.S multiple myeloma cells, and this degradation process is proteasome-dependent; co-treatment with 1 μM bortezomib or 1 μM MG132 followed by a 2-hour incubation restores IRF4 levels[1]. dIRF4-2 (2.5 μM; 4 h) induces highly selective degradation of IRF4 in MM1.S multiple myeloma cells, and exerts no significant effects on other IRF family members or novel CRBN substrates after 4 h of treatment at 2.5 μM[1]. dIRF4-2 (100 μM three-fold dilution series; 96 h, with second dose at 48 h) induces potent, IRF4-dependent cytotoxicity in all tested multiple myeloma cell lines after 96 h of treatment (IC50 0.68-8 μM), while exerting no effect on IRF4-independent HEK293T cells (IC50 > 50 μM)[1].
References:
[1]. Agius MP, et al. Pharmacological targeting of IRF4 as a therapeutic strategy for multiple myeloma. Nat Chem Biol. 2026 May 28.