PLX263376

GSE109985: Genome-wide transcriptional profiles for the GSK3 selective inhibitor BRD0507 and for the GSK3/ dual inhibitor BRD0320

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

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 GSK3 selective inhibitor BRD0507 and for the GSK3/ 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 GSK3/ 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 -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 GSK3 or GSK3 individually does not increase -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 Asp133Glu196 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 GSK3 and GSK3 selective inhibitors provided insights into GSK3 targeting in AML where GSK3 has been identified as a therapeutic target using genetic approaches. Our GSK3 selective compound (BRD0705) inhibits kinase function and does not stabilize -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 GSK3 inhibition offering a promising therapeutic approach in AML. SOURCE: Gabriela Alexe (galexe@broadinstitute.org) - Broad Institute