Glycogen synthase kinase 3β (GSK3β), a serine threonine kinase, which is aberrantly overexpressed in cancer and Alzheimer’s disease. A small set of 86 fragments was derived from three different pathways using a diversity-oriented synthesis approach and screened against GSK3β by differential scanning fluorimetry (DSF). Compounds that scored in this assay served as starting points for SAR studies in a variety of assays and ultimately lead to the growth of a more potent fragment. 15R, the compound that displayed the greatest thermal stabilization against GSK3β, occupies the ATP-binding site (x-ray crystallography) with Kd = 9.1 μM (isothermal calorimetry, ITC) and demonstrates a 50-fold selectivity against a closely related kinase (CDK5). ACS Med. Chem. Lett., 2016, 7(9), 852-856.