Identifying small molecules that induce the disruption of constitutive protein-protein interfaces is a challenging objective. Here, a targeted biophysical screening cascade was employed to specifically identify small molecules that could disrupt the constitutive, homodimeric protein-protein interface within CK2β. This approach could potentially be applied to achieve subunit disassembly of other homo-oligomeric proteins as a means of modulating protein function.This research was supported by the Agency for Science, Technology and Research (A*STAR) Singapore (Ph.D. sponsorship, W.G.S.) and the Wellcome Trust Strategic Award (090340/Z/09/Z)