IKZF2-degrader 2

IKZF2-degrader 2 is a selective, orally active molecular glue degrader for IKZF2, with DC50 values of 0.5 nM (HiBit) and 1.8 nM (FACS). It facilitates ubiquitination and degradation of target proteins by recruiting the CRL4-CRBN E3 ubiquitin ligase. IKZF2-degrader 2 shows moderate degradation activity against SALL4 (DC50 of 9 nM) but does not significantly degrade IKZF1, IKZF3, CK1α, or GSPT1. This compound is suitable for research in cancer immunology.

IZKF2:0.5 nM (DC50)

IKZF2-degrader 2 (Compound 55) is a highly selective IKZF2 degrader with minimal off-target degradation of new substrates in Jurkat cells. At a concentration of 1 μM, it exhibits exceptional metabolic stability in human, cynomolgus monkey, rat, and mouse liver microsomes, particularly in humans. Western blot analysisusing Jurkat cells and CRBN knockout (KO) Jurkat cells showed that at concentrations of 41, 123, 370, 1111, 3333, and 10000 nM, with an incubation time of 6 hours, IKZF2 was selectively degraded without affecting IKZF1, CK1α, or GSPT1. The activity was entirely lost in CRBN KO cells, confirming CRBN-mediated activity.

Compound 55, also known as IKZF2-degrader 2, administered as a single dose through intragastric administration (10-30 mg/kg, i.g., single dose), is capable of achieving potent and sustained degradation of the IKZF2 protein in immune organs.