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Genome-wide analysis of gene expression in mouse embryonic stem cells when individual glycogen synthase kinase 3 (GSK3) paralog is inhibited via chemical genetic approach

ABSTRACT: Analysis of downstream targets when individual GSK3 paralog is inhibited at gene expression level. The hypothesis tested in the present study was that GSK3α and GSK3β have different targets. Results provide important information of the downstream targets of GSK3α and GSK3β.

ORGANISM(S): Mus musculus

PROVIDER: GSE98080 | GEO | 2018/02/21

REPOSITORIES: GEO

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Project description:Exploiting an Asp-Glu “switch” in glycogen synthase kinase 3 to design paralog selective inhibitors for use in acute myeloid leukemia: Genome-wide transcriptional profile for the GSK3β selective inhibitor BRD3731. Glycogen synthase kinase 3 (GSK3), a key regulatory kinase in the WNT pathway, remains a therapeutic target of interest in many diseases. While dual GSK3α/β inhibitors have entered clinical trials, none has successfully translated to clinical application. Mechanism-based toxicities, driven in part by the inhibition of both GSK3 paralogs and subsequent β-catenin stabilization, are a concern in the translation of this target class to cancer therapy, particularly for the treatment of acute myeloid leukemia (AML). Knockdown of GSK3α or GSK3β individually does not increase β-catenin in certain cellular subtypes and offers a conceptual resolution to targeting GSK3: paralog-selective inhibition. However, only inadequate chemical tools exist. The design of selective ATP competitive inhibitors poses a drug discovery challenge due to the high homology (95% identity, 100% similarity) in their ATP binding domains. Taking advantage of an Asp133®Glu196 “switch” in their hinge binding domains, we present a rational design strategy towards the discovery of a paralog selective set of GSK3 inhibitors. These first-in-class GSK3α and GSK3β selective inhibitors provided insights into GSK3 targeting in AML where GSK3α has been identified as a therapeutic target using genetic approaches. Our GSK3α selective compound (BRD0705) inhibits kinase function and does not stabilize β-catenin, mitigating potential neoplastic concerns. BRD0705 induces myeloid differentiation and impairs colony formation in AML cells while no effect is observed on normal hematopoietic cells. Moreover, BRD0705 impairs leukemia initiation and prolongs survival in AML mouse models. These studies validate feasibility of paralog selective GSK3α inhibition offering a promising therapeutic approach in AML.

Project description:Exploiting an Asp-Glu “switch” in glycogen synthase kinase 3 to design paralog selective inhibitors for use in acute myeloid leukemia: Genome-wide transcriptional profiles for the GSK3α selective inhibitor BRD0507 and for the GSK3α/β dual inhibitor BRD0320 Glycogen synthase kinase 3 (GSK3), a key regulatory kinase in the WNT pathway, remains a therapeutic target of interest in many diseases. While dual GSK3α/β inhibitors have entered clinical trials, none has successfully translated to clinical application. Mechanism-based toxicities, driven in part by the inhibition of both GSK3 paralogs and subsequent β-catenin stabilization, are a concern in the translation of this target class to cancer therapy, particularly for the treatment of acute myeloid leukemia (AML). Knockdown of GSK3α or GSK3β individually does not increase β-catenin in certain cellular subtypes and offers a conceptual resolution to targeting GSK3: paralog-selective inhibition. However, only inadequate chemical tools exist. The design of selective ATP competitive inhibitors poses a drug discovery challenge due to the high homology (95% identity, 100% similarity) in their ATP binding domains. Taking advantage of an Asp133®Glu196 “switch” in their hinge binding domains, we present a rational design strategy towards the discovery of a paralog selective set of GSK3 inhibitors. These first-in-class GSK3α and GSK3β selective inhibitors provided insights into GSK3 targeting in AML where GSK3α has been identified as a therapeutic target using genetic approaches. Our GSK3α selective compound (BRD0705) inhibits kinase function and does not stabilize β-catenin, mitigating potential neoplastic concerns. BRD0705 induces myeloid differentiation and impairs colony formation in AML cells while no effect is observed on normal hematopoietic cells. Moreover, BRD0705 impairs leukemia initiation and prolongs survival in AML mouse models. These studies validate feasibility of paralog selective GSK3α inhibition offering a promising therapeutic approach in AML.

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Genome-wide analysis of gene expression in mouse embryonic stem cells when individual glycogen synthase kinase 3 (GSK3) paralog is inhibited via chemical genetic approach

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