Pharmacophoric Fragment-based Design And Biological Evaluation Of 2-propenone Derivatives As Novel Anti-cancer CK2 Inhibitors

Cancer is threatening the life of human.Protein kinase CK2 has been regarded as a cancer therapeutic target due to its growth-promoting and anti-apoptotic.However,most of its ATP competitive inhibitors fail to be the drug candidates due to their low selectivity and side-effect defects.For the compounds with polycyclic scaffolds,it is the challengeable work to be optimized to overcome their drawbacks.Therefore,the molecules with linear scaffolds are considered as the CK2 inhibitors candidates.This thesis focused on the discovery of novel 2-propenone derivates as anti-cancer CK2inhibitors with the the fragment-based assembling strategy.1.Pharmacophoric fragments library targeting the sub-pocket of CK2αPharmacophoric fragments are the necessary units of the bioactive compounds.By considering the fragments scaffolds and structure features of ATP-binding pocket of CK2,the inhibitors with diverse molecular scaffolds and potent inhibitory activity were decomposed into virtual fragments.Further,molecular docking was performed to predict the binding mode and affinity of these fragments with CK2α,and the fragment library targeting three sub-pockets were constructed.These results provide the active fragment resources for pharmacophore fragment-based drug design.2.Binding mode of Isoliquiritigenin with CK2αand its derivatives designThe binding mode of Isoliquiritigenin（ISL）with CK2αwas elucidated based on the results of molecular docking and molecular dynamics simulation.The two aromatic rings of ISL were sandwiched into the hydrophobic core of ATP-binding pocket.The carbonyl oxygen in the 2-propenone scaffold of ISL occupied a similar position to the N atoms of the thiazole in 3b and pyridine in CX-4945,being able toact as a hydrogen bond acceptor to the-NH group of Val116.The 2-hydroxyl group of ISL binds near the hinge region but may form an intra-molecular hydrogen bond with its neighboring carbonyl roup.Furthermore,the-OH group of the p-phenol of this compound interacts with Lys68 through polar interactions.Our modeling data suggests that other compounds with linear scaffolds can mimic ISL’s interactions with both the hinge and positive regions.And eight compounds with the different pharmocophore groups linked to the 2-propenone scaffold were designed.3.Synthesis and biological activity evaluation of 2-propenone derivativesA series of novel compounds containing 2-aminothiazole,2-amino-1,3,4-thiadiazole,2-aminopyrazole and 3-aminopyrazole groups with 2-propenone scaffold were synthesized and evaluated for their CK2 inhibition and anti-cacer activity.The bioactivity evaluation showed that the 2-aminopyrazole compound exhibited a good inhibitory activity,and the NH of 2-aminopyrazole could better interact with the hinge region residue.Compound 8a was found to be the most potent CK2 inhibitor(IC₅₀=0.6 u M)with the anti-proliferative activity on Hep G2 cancer cells（IC50=14 u M）,compared to the activity of isoliquiritigenin(IC₅₀=17 u M and 51 u M,respectively).Molecular docking was performed to understand the binding modes of the newly designed 2-propenone derivatives with CK2.Compound 8a 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.In summary,a series of novel 2-propenone derivatives were designed,synthesized and evaluated for their in vitro CK2 inhibition and anti-cancer activity.These results provides an important theoretical basis and hints for the development of CK2 new anticancer drugs.