The GSK3α-selective inhibitor BRD0705 promotes AML cell differentiation without increasing β-catenin.

  • Major finding: The GSK3α-selective inhibitor BRD0705 promotes AML cell differentiation without increasing β-catenin.

  • Approach: Targeting the Asp-Glu switch in the kinase hinge allows design of selective GSK3α and GSK3β inhibitors.

  • Impact: Selective GSK3α inhibition may be feasible and beneficial for the treatment of patients with AML.

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Glycogen synthase kinase 3α (GSK3α) has emerged as a potential therapeutic target in acute myeloid leukemia (AML), as its genetic suppression promotes AML cell differentiation and reduces leukemic progression. However, selective GSK3α inhibitors are lacking. The ATP-binding site of GSK3α is highly similar to its paralog GSK3β, sharing 95% identity. Thus, previous ATP-competitive inhibitors target both GSK3α and GSK3β, and these dual inhibitors stabilize β-catenin, promote myeloid cell transformation, and exhibit mechanism-based toxicities. Wagner, Benajiba, and colleagues sought to develop paralog-specific GSK3 inhibitors targeting the Asp-Glu “switch” in the kinase hinge, the single amino acid difference in the ATP-binding domain with a Glu in GSK3α and an Asp in GSK3β. Structure-based design yielded the GSK3α-selective inhibitor BRD0705 and the GSK3β-selective inhibitor BRD3731. GSK3α inhibition with BRD0705 did not stabilize β-catenin in AML cells, whereas BRD3731 did in a subset of AML cell lines. GSK3α inhibition with BRD0705 effectively suppressed GSK3α kinase activity, induced differentiation, and impaired colony formation in AML cell lines and primary cells. In contrast, the effects of BRD3731 were inconsistent, indicating that GSK3α-selective inhibition may be beneficial in AML. RNA sequencing revealed that BRD0705 induced expression of differentiation transcriptional programs and downregulated stemness gene signatures without increasing the β-catenin transcriptional signature. Conversely, the dual inhibitor BRD0320 strongly induced β-catenin signaling pathway genes, further demonstrating that inhibition of GSK3α and GSK3β have different effects. In vivo, BRD0705 suppressed AML growth and extended survival in xenografts and syngeneic mouse models with no apparent toxicity to normal hematopoietic cells. In addition to providing insight into the paralog-specific functions of GSK3α and GSK3β, these findings suggest that GSK3α inhibition may be a feasible therapeutic approach in patients with AML.

Wagner FF, Benajiba L, Campbell AJ, Weïwer M, Sacher JR, Gale JP, et al. Exploiting an Asp-Glu “switch” in glycogen synthase kinase 3 to design paralog-selective inhibitors for use in acute myeloid leukemia. Sci Transl Med 2018;10:eaam8460.

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