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Dual IKZF2 and CK1α degrader targets acute myeloid leukemia cells
Sun-Mi Park1, David K Miyamoto2, Grace Y Q Han1
1Molecular Pharmacology Program and Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Abstract:
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 1α (CK1α), 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 contributes to myeloid leukemogenesis. DEG-35 possesses additional substrate specificity for the therapeutically relevant target CK1α, which was identified through unbiased proteomics and a PRISM screen assay. Degradation of IKZF2 and CK1α blocks cell growth and induces myeloid differentiation in AML cells through CK1α-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 CK1α to enhance efficacy against AML that may be expanded to additional targets and indications.
Insights
Researchers developed novel degraders, DEG-35 and DEG-77, targeting IKZF2 and casein kinase 1α (CK1α) to treat acute myeloid leukemia (AML). These compounds show promise in delaying leukemia progression in preclinical models.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Acute myeloid leukemia (AML) is a significant hematologic malignancy.
- Epigenetic regulators are emerging as crucial therapeutic targets in AML.
- Targeting specific proteins involved in leukemogenesis is a key strategy.
Purpose of the Study:
- To develop novel cereblon-dependent degraders targeting IKZF2 and casein kinase 1α (CK1α).
- To evaluate the efficacy of these degraders in blocking AML cell growth and inducing differentiation.
- To assess the therapeutic potential of these degraders in preclinical AML models.
Main Methods:
- Structure-guided design was employed to create DEG-35, a degrader of IKZF2.
- Unbiased proteomics and PRISM screening identified CK1α as an additional target for DEG-35.
- Murine and human AML mouse models were used to test the efficacy of DEG-35 and DEG-77.
Main Results:
- DEG-35 demonstrated nanomolar degradation of IKZF2 and also targeted CK1α.
- Degradation of IKZF2 and CK1α inhibited AML cell proliferation and promoted myeloid differentiation.
- Treatment with DEG-35 or DEG-77 significantly delayed leukemia progression in vivo.
Conclusions:
- A strategy for multitargeted protein degradation of IKZF2 and CK1α offers enhanced efficacy against AML.
- DEG-35 and DEG-77 represent promising therapeutic candidates for AML treatment.
- This approach may be applicable to other targets and cancer indications.
