MGD-22 is a molecular glue and orally active degrader of IKZF1/2/3, with DC50 values of 8.33 nM, 9.91 nM, and 5.74 nM, respectively. It exhibits strong anti-proliferative activity against various hematological cancer cells and induces cell apoptosis (apoptosis). MGD-22 demonstrates significant anti-tumor efficacy in mice with NCI-H929 or WSU-DLCL-2 xenografts. This compound is useful for researching blood cancers, including multiple myeloma (MM), acute myeloid leukemia (AML), and diffuse large B-cell lymphoma (DLBCL).

IKZF1:8.33 nM (DC50)

MGD-22 exhibits significant antiproliferative activity against multiple myeloma (MM) cell lines, including NCI-H929 (IC50 = 7.93 nM), RPMI-8226 (IC50 = 83.2 nM), and OPM-2 (IC50 = 7.87 nM); acute myeloid leukemia (AML) cell lines, such as MV-4-11 (IC50 = 5.38±0.43 nM), U937 (IC50 = 15.1 nM), MOLM-13 (IC50 = 196 nM), KG-1 (IC50 = 78.9 nM), Skm-1 (IC50 = 218 nM), MUTZ-1 (IC50 = 148 nM); and diffuse large B-cell lymphoma (DLBCL) cell lines, including WSU-DLCL-2 (IC50 = 8.99 nM), Ocl-Ly3 (IC50 = 95.3 nM), SU-DHL-4 (IC50 = 452 nM), TMD8 (IC50 = 87.7 nM), U2932 (IC50 = 8.17 nM), with negligible activity against normal peripheral blood mononuclear cells (PBMCs) and primary B cells (IC50 > 33 μM). MGD-22 (0.01-10 μM, 72 h) induces dose-dependent apoptosis in NCI-H929 and MV-4-11 cells. It selectively promotes potent degradation of IKZF1/2/3 in HEK293T cells transfected with IKZF1/2/3-HiBit tags (DC50 of 8.33 nM, 9.91 nM, and 5.74 nM, respectively, with Dmax of 94.33%, 91.58%, and 92.26%). Additionally, MGD-22 (1 μM, 24 h) facilitates the formation of a ternary complex between IKZF1/2/3 and CRBN in NCI-H929 cells.

MGD-22 (3-10 mg/kg, administered orally once daily for 14 days) demonstrated significant antitumor activity in NOD/SCID mice with NCI-H929 xenografts. When combined with Ibrutinib or Venetoclax, MGD-22 (5 mg/kg, orally administered once daily for 36 days) exhibited synergistic antitumor effects in mice with WSU-DLCL-2 xenografts.