Protein　kinase　CK2　has　emerged　as　an　attractive　cancer　therapeutic　target.　Previous　studies　have　highlighted　the　challenge　of　optimizing　CK2　ATP-competitive　inhibitors　that　have　low　druggability　due　to　their　polycyclic　ring　scaffolds.　Therefore　the　development　of　novel　inhibitors　with　non-polycyclic　scaffolds　emerges　as　a　promising　strategy　for　drug　discovery　targeting　CK2.　In　this　current　study,　based　on　the　similar　predicted　binding　poses　of　the　linear　2-propenone　scaffold　of　isoliquiritigenin　with　that　of　the　polycyclic　inhibitor　CX-4945,　a　series　of　2-propenone　derivatives　containing　an　amine-substituted　five-membered　heterocycle　and　a　benzoic　acid　were　designed,　synthesized　and　evaluated　for　their　in　vitro　CK2　inhibition　and　anti-cancer　activity.　Compound　8b　was　found　to　be　the　most　potent　CK2　inhibitor　(IC50　=　0.6　mu　M)　with　the　anti-proliferative　activity　on　HepG2　cancer　cells　(IC50　=　14　mu　M),　compared　to　the　activity　of　isoliquiritigenin　(IC50　=　17　mu　M　and　51　mu　M,　respectively).　Molecular　docking　was　performed　to　understand　the　binding　modes　of　the　newly　designed　2-propenone　derivatives　with　CK2.　Compound　8b　formed　the　most　favorable　network　of　hydrogen　bonds　with　both　the　hinge　region　and　positive　area.　Our　results　indicate　that　CK2　derivatives　with　a　linear　2-propenone　scaffold　are　promising　candidates　for　anti-cancer　drug　discovery.　(C)　2019　Elsevier　Inc.　All　rights　reserved.