BRD0705

BRD0705 is a first-in-class, potent, and paralog-selective small molecule inhibitor of Glycogen Synthase Kinase 3 alpha (GSK3α). It was rationally designed to exploit a single amino acid difference in the hinge binding domain between GSK3α (Glu196) and GSK3β (Asp133). By selectively targeting the alpha paralog, BRD0705 avoids the stabilization of β-catenin and subsequent WNT pathway activation, which is a major toxicity concern associated with dual GSK3α/β inhibitors. In preclinical models of acute myeloid leukemia (AML), BRD0705 promotes myeloid differentiation, reduces transcriptional programs of stemness, and impairs leukemia initiation. The compound is orally bioavailable and has demonstrated efficacy in multiple AML mouse models, including xenograft and syngeneic systems, without significant toxicity to normal hematopoietic cells.