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Genes regulated by DEG-35, a dual degrader of IKZF2 and CK1A in AML cells

ABSTRACT: To investigate the genes regulated in MOLM-13 cells treated with DMSO or DEG-35, a dual degrader of IKZF2 and CK1A in AML cells

ORGANISM(S): Homo sapiens

PROVIDER: GSE220707 | GEO | 2023/01/16

REPOSITORIES: GEO

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Dual IKZF2 and CK1α degrader targets acute myeloid leukemia cells

Project description: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 1 alpha (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 cell lines through CK1α–p53- and IKZF2-dependent pathways. Target degradation by DEG-35 or the analog DEG-77 delays leukemia progression in murine and human AML mice models. Overall, we provide a strategy for multi-targeted degradation of IKZF2/CK1α to enhance efficacy against AML that may be expanded to additional targets and indications.

2023-03-08 | PXD039474 | Pride

Design and development of IKZF2 and CK1α dual degraders

Project description:Lenalidomide achieves its therapeutic efficacy by recruiting and removing proteins of therapeutic interest through the E3 ligase substrate adapter cereblon. Here, we report the rational design and characterization of 81 cereblon ligands for their ability to degrade the transcription factor Helios (IKZF2) and casein kinase 1 alpha (CK1α) in acute myeloid leukemia MOLM-13 cells. Using a structure-based approach, we identified a key naphthamide scaffold that depleted both intended targets. Structure-activity relationship studies for degradation of the desired targets over other targets (IKZF1, GSPT1) afforded an initial lead compound, termed DEG-35. A subsequent scaffold replacement campaign informed by degradation profiles against a panel of substrates identified DEG-77, which selectively degrades IKZF2 and CK1α, and possesses suitable pharmacokinetic properties, solubility, and selectivity for in vivo studies. Finally, we show that DEG-77 has antiproliferative activity in diffuse large B cell lymphoma (DLBCL) cell line OCI-LY3 and ovarian cancer cell line A2780, indicating that these dual degraders and their targets may have efficacy against additional cancer types.

2024-01-04 | PXD045327 | Pride

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Project description:IKZF2 is an important nuclear matrix protein and plays a pivotal role in T cell development and differentiation, while its expression and function in Cutaneous T cell lymphoma (CTCL) remain ambiguous. Our study aimed to investigate the expression pattern, biological function of IKZF2 in a large clinical cohort. IKZF2 is specifically over-expressed in malignant T cells with MF tumor-stage. In order to explore the function of IKZF2 in the pathogenesis of CTCL, transcriptome sequencing was performed among Hut78 cells transfected with shRNAs targeting IKZF2 (shIKZF2) and scrambled shRNA(sh0) to investigate genes regulated by IKZF2 in CTCL cells .

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2023-07-18 | GSE211758 | GEO

Single cell transcriptional profiles of control and Ikzf2-transfected mouse cochlear cells

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IKZF2 is required for myeloid leukemic stem cells by driving self-renewal and inhibiting the myeloid differentiation program II

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IKZF2 is required for myeloid leukemic stem cells by driving self-renewal and inhibiting the myeloid differentiation program I

2017-12-21 | GSE108367 | GEO

Gene expression in mouse splenic CD4+CD25+ (Treg) cells from Ikzf2-/-, Ikzf4-/- and double Ikzf2-/-Ikzf4-/- (dKO) mice

Project description:CD4+CD25+ cells were sorted from the spleen of 6-7 week old mice WT, Ikzf4-/- and dKO mice (group 1) were processed separately from a a second group (group2) containing Ikzf2-/- and their WT controls. Group 1 originates from an ultra clean sterile bioBubble, while group 2 originates from a specific pathogne free facility. In each group 3 samples were analyzed for each genotype.

2023-10-24 | GSE162023 | GEO

pan-Kinase degrader response time course

Project description:Targeted protein degradation (TPD) refers to the use of small molecules to induce ubiquitin-dependent degradation of proteins. These degrader molecules are of great interest in drug development as they can address previously inaccessible targets. However, degrader discovery and optimization remains an inefficient and empirical process due to a lack of understanding of the key molecular events required to successfully induce target degradation. Here we used a time-course experiment to assess the transcriptional response to rapid pan-Kinase degradation.

2020-09-07 | GSE157560 | GEO

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