A focused library of furanopyrimidine (350 compounds) was rapidly synthesized in parallel reactors and in situ screened for Aurora and epidermal growth factor receptor (EGFR) kinase activity, leading to the identification of some interesting hits. On the basis of structural biology observations, the hit 1a was modified to better fit the back pocket, producing the potent Aurora inhibitor 3 with submicromolar antiproliferative activity in HCT-116 colon cancer cell line. On the basis of docking studies with EGFR hit 1s, introduction of acrylamide Michael acceptor group led to 8, which inhibited both the wild and mutant EGFR kinase and also showed antiproliferative activity in HCC827 lung cancer cell line. Furthermore, the X-ray cocrystal study of 3 and 8 in complex with Aurora and EGFR, respectively, confirmed their hypothesized binding modes. Library construction, in situ screening, and structure-based drug design (SBDD) strategy described here could be applied for the lead identification of other kinases.

HTS hit 7 was modified through hybrid design strategy to introduce a chiral side chain followed by introduction of Michael acceptor group to obtain potent EGFR kinase inhibitors 11 and 19. Both 11 and 19 showed over 3 orders of magnitude enhanced HCC827 antiproliferative activity compared to HTS hit 7 and also inhibited gefitinib-resistant double mutant (DM, T790M/L858R) EGFR kinase at nanomolar concentration. Moreover, treatment with 19 shrinked tumor in nude mice xenograft model.

Overall, the findings in this study suggest that ATA is able to effectively inhibit EV71 replication through interfering with the viral 3D polymerase.

The further development of electrode materials with high capacity and excellent rate capability presents a great challenge for advanced lithium-ion batteries. Herein, we demonstrate a battery-capacitive synchronous lithium storage mechanism based on a scrupulous design of TiC/NiO core/shell nanoarchitecture, in which the TiC nanowire core exhibits a typical double-layer capacitive behavior, and the NiO nanosheet shell acts as active materials for Li(+) storage. The as-constructed TiC/NiO (32 wt % NiO) core/shell nanoarchitecture offers high overall capacity and excellent cycling ability, retaining above 507.5 mAh g(-1) throughout 60 cycles at a current density of 200 mA g(-1) (much higher than theoretical value of the TiC/NiO composite). Most importantly, the high rate capability is far superior to that of NiO or other metal oxide electrode materials, owing to its double-layer capacitive characteristics of TiC nanowire and intrinsic high electrical conductivity for facile electron transport during Li(+) storage process. Our work offers a promising approach via a rational hybridization of two electrochemical energy storage materials for harvesting high capacity and good rate performance.

Herein we reveal a simple method for the identification of novel Aurora kinase A inhibitors through substructure searching of an in-house compound library to select compounds for testing. A hydrazone fragment conferring Aurora kinase activity and heterocyclic rings most frequently reported in kinase inhibitors were used as substructure queries to filter the in-house compound library collection prior to testing. Five new series of Aurora kinase inhibitors were identified through this strategy, with IC(50) values ranging from approximately 300 nM to approximately 15 microM, by testing only 133 compounds from a database of approximately 125,000 compounds. Structure-activity relationship studies and X-ray co-crystallographic analysis of the most potent compound, a furanopyrimidine derivative with an IC(50) value of 309 nM toward Aurora kinase A, were carried out. The knowledge gained through these studies could help in the future design of potent Aurora kinase inhibitors.