DEG-35 is a potent, cereblon-dependent, dual degrader of IKZF2 (DC50=4.4 nM, DCmax=92%) and casein kinase 1α (CK1α, DC50=1.4 nM, DCmax=84%), shows leukemic cell killing activity.
DEG-35 efficiently degrades IKZF2 with limited activity against IKZF1, IKZF3 and IKZF4 in a Cullin-dependent manner.
DEG-35 inhibits growth activity in a panel of AML cell lines representing various oncogenic mutations with IC50 values from single digit nM to low μM concentrations (MOLM-13 cell, IC50=5.3 nM).
DEG-35 degrades dual targets IKZF2 and CK1α via Cullin-CRBN dependent pathway.
DEG-35 has higher affinity (KD = 472.6 nM) than lenalidomide (KD = 804.7 nM) for CRBN, as measured by HTR-FRET.
DEG-35 activates the p53 apoptosis pathway, activates IKZF2-dependent differentiation in MOLM-13 cells.
DEG-35 has preferential cytotoxic activity in AML cells compared to normal cells.
DEG-35 can degrade targets in AML cells in vivo and delay leukemia progression in the MLL-AF9 CrbnI391V mice model.