Dual IKZF2 and CK1a degrader targets acute myeloid leukemia cells

Acute myeloid leukemia (AML) is a hematologic malignancy for which several epigenetic regulators have been identified as therapeutic targets. Here we report the development of cereblon-dependent degraders of IKZF2 and casein kinase 1a (CK1a), termed DEG-35 and DEG-77. We utilized a structure-guided approach to develop DEG-35 as a nanomolar degrader of IKZF2, a hematopoietic-specific transcription factor that con-tributes to myeloid leukemogenesis. DEG-35 possesses additional substrate specificity for the therapeuti-cally relevant target CK1a, which was identified through unbiased proteomics and a PRISM screen assay. Degradation of IKZF2 and CK1a blocks cell growth and induces myeloid differentiation in AML cells through CK1a-p53-and IKZF2-dependent pathways. Target degradation by DEG-35 or a more soluble analog, DEG -77, delays leukemia progression in murine and human AML mouse models. Overall, we provide a strategy for multitargeted degradation of IKZF2 and CK1a to enhance efficacy against AML that may be expanded to additional targets and indications.