IKZF2 degrader 25 is a potent, highly selective, and orally efficacious IKZF2 degrader with DC50 of 1.78 nM (Dmax = 93.2%, HEK293T cells), with minimal IKZF1/3 degradation.
IKZF2 degrader 25 potently degraded endogenous IKZF2 in Jurkat cells with a DC50 of 1.59 nM and Dmax of 92.2%, demonstrating markedly higher potency than DKY709 (DC50 = 9.56 nM, Dmax = 80.5%) and pomalidomide (DC50 > 10,000 nM, Dmax = 40.7%).
IKZF2 degrader 25 elicited dose-dependent decreases of endogenous IKZF2 and near-complete degradation was achieved by compound 25 (100 nM) at 24 h in Jurkat cells.
IKZF2 degrader 25 shows minimal degradation effects on IKZF1, IKZF3, SALL4, GSPT1, CK1α and ZFP91.
IKZF2 degrader 25 promotes the formation of a stable ternary complex between IKZF2 and CRBN to drives its robust degradation. exhibited IKZF2 degradation activity via a Cullin-CRBN dependent pathway.
IKZF2 degrader 25 increased interferon-γ (IFNγ) production in exhausted CD4+ and CD8+ effector T cells (Teffs), modulated the phenotype and function of Treg cells, thereby enhancing antitumor T cell-mediated immunity.
IKZF2 degrader 25 significantly suppressed tumor growth and showed synergistic anticancer efficacy with anti-PD-1 therapies, in B16F cell xenograft tumor model.