Novel CK2 inhibitors among benzylidenebenzofuran-3(2H)-one (aurone) derivatives have been identified. A series of aurones have been synthesized. These compounds are structurally related to synthetic flavones and showed nanomolar activities towards CK2. Biochemical tests revealed 20 newly synthesized compounds inhibited CK2 with IC50 values in the nanomolar range. Further property-based optimization of aurones was performed, yielding a series of CK2 inhibitors with enhanced lipophilic efficiency. The most potent compound 12m (BFO13) has CLipE = 4.94 (CLogP = 3.5; IC50 = 3.6 nM) commensurable with the best known inhibitors of CK2. The binding mode for compounds in this class with ATP-binding site of CK2 has been proposed (Fig. 1).