MGD-22 is a potent, selective and triple Ikaros proteins IKZF1/2/3 degrader with DC50 of 8.33/9.91/5.74 nM respectively in NCI-H929 cells, all Emax>90%.
MGD-22 (1 μM) for 4 h caused substantial reductions in IKZF1 (>60%), IKZF2 (>60%), and IKZF3 (>80%).
MGD-22 achieved potent endogenous degradation of IKZF1/2/3 in NCI-H929 and MV-4-11 cells, demonstrating markedly higher potency than pomalidomide.
MGD-22 showed minimal degradation effects on SALL4 and PLZF as well as RAB28, IRF4, ZMYM2.
MGD-22 exhibited potent inhibitory efficacy (IC50=6.8-9.6 nM) in pomalidomide-resistant NCI-H929, MV-4-11 and WSU-DLCL-2 cells.
MGD-22 promotes the formation of a robust ternary complex between IKZF1/2/3 and CRBN, thereby driving their efficient degradation.
MGD-22 mediates IKZF1/2/3 degradation through a Cullin-CRBN-dependent mechanism.
MGD-22 (3 and 10 mg/kg, oral gavage) significantly inhibited the growth of NCI-H929 xenograft tumors.
MGD-22 displayed significant synergistic effects when combined with BTK and BCL2 inhibitor in DLBCL models, respectively.