BRD3731

BRD3731 is a first-in-class, paralog-selective small molecule inhibitor of glycogen synthase kinase 3 beta (GSK3β). Developed by researchers at the Broad Institute, it belongs to a pyrazolo-tetrahydroquinolinone chemical series designed to exploit a single amino acid difference (Asp133 in GSK3β versus Glu196 in GSK3α) within the hinge binding domain of the kinase. BRD3731 demonstrates approximately 14-fold selectivity for GSK3β over its paralog GSK3α, with an IC50 of 15 nM against GSK3β compared to 215 nM for GSK3α. In preclinical studies, particularly in models of acute myeloid leukemia (AML), BRD3731 serves as a critical chemical probe to differentiate the biological roles of GSK3 paralogs. Unlike GSK3α-selective inhibitors, GSK3β inhibition by BRD3731 has been shown to induce β-catenin stabilization in a context-dependent manner, which may have oncogenic implications in certain myeloid leukemia settings.