Polo-like kinase(PLK1) has been identified as a potential target for cancer treatment.Although a number of small molecules have been investigated as PLK1 inhibitors, many of which showed limited selectivity. PLK1 harb...Polo-like kinase(PLK1) has been identified as a potential target for cancer treatment.Although a number of small molecules have been investigated as PLK1 inhibitors, many of which showed limited selectivity. PLK1 harbors a regulatory domain, the Polo box domain(PBD), which has a key regulatory function for kinase activity and substrate recognition. We report on 3-bromomethylbenzofuran-2-carboxylic acid ethyl ester(designated: MCC1019) as selective PLK1 inhibitor targeting PLK1 PBD. Cytotoxicity and fluorescence polarization-based screening were applied to a library of 1162 drug-like compounds to identify potential inhibitors of PLK1 PBD. The activity of compound MC1019 against the PLK1 PBD was confirmed using fluorescence polarization and microscale thermophoresis.This compound exerted specificity towards PLK1 over PLK2 and PLK3. MCC1019 showed cytotoxic activity in a panel of different cancer cell lines. Mechanistic investigations in A549 lung adenocarcinoma cells revealed that MCC1019 induced cell growth inhibition through inactivation of AKT signaling pathway, it also induced prolonged mitotic arrest—a phenomenon known as mitotic catastrophe, which is followed by immediate cell death via apoptosis and necroptosis. MCC1019 significantly inhibited tumor growth in vivo in a murine lung cancer model without affecting body weight or vital organ size, and reduced the growth of metastatic lesions in the lung. We propose MCC1019 as promising anti-cancer drug candidate.展开更多
A method Green function satisfying of three-dimensional time domain linear conditions at free surface and body surface boundary was employed to analyze the wave resistance and wave profile of a displacement multi-hull...A method Green function satisfying of three-dimensional time domain linear conditions at free surface and body surface boundary was employed to analyze the wave resistance and wave profile of a displacement multi-hull ship. The wave profile induced by a moving time domain point source was compared with those by a Havelock source, and satisfactory results were obtained. The panel method based on the time domain source distribution on the ship mean wetted hull surface was used to perform the wave making com- putations tbr mono-hull ships, catamaran and trimaran. Reasonable results were also obtained. Using the numerical method the wave profile simulations of multi-hull ships for a given Froude number were conducted.展开更多
基金partly supported by the Deutsche Forschungsgemeinschaft(DFG INST 268/281-1 FUGG and BE 4572/3-1,Germany)
文摘Polo-like kinase(PLK1) has been identified as a potential target for cancer treatment.Although a number of small molecules have been investigated as PLK1 inhibitors, many of which showed limited selectivity. PLK1 harbors a regulatory domain, the Polo box domain(PBD), which has a key regulatory function for kinase activity and substrate recognition. We report on 3-bromomethylbenzofuran-2-carboxylic acid ethyl ester(designated: MCC1019) as selective PLK1 inhibitor targeting PLK1 PBD. Cytotoxicity and fluorescence polarization-based screening were applied to a library of 1162 drug-like compounds to identify potential inhibitors of PLK1 PBD. The activity of compound MC1019 against the PLK1 PBD was confirmed using fluorescence polarization and microscale thermophoresis.This compound exerted specificity towards PLK1 over PLK2 and PLK3. MCC1019 showed cytotoxic activity in a panel of different cancer cell lines. Mechanistic investigations in A549 lung adenocarcinoma cells revealed that MCC1019 induced cell growth inhibition through inactivation of AKT signaling pathway, it also induced prolonged mitotic arrest—a phenomenon known as mitotic catastrophe, which is followed by immediate cell death via apoptosis and necroptosis. MCC1019 significantly inhibited tumor growth in vivo in a murine lung cancer model without affecting body weight or vital organ size, and reduced the growth of metastatic lesions in the lung. We propose MCC1019 as promising anti-cancer drug candidate.
基金Project supported by China Shipbuilding Indudustry Corporation (Grant No:J40.4.4).
文摘A method Green function satisfying of three-dimensional time domain linear conditions at free surface and body surface boundary was employed to analyze the wave resistance and wave profile of a displacement multi-hull ship. The wave profile induced by a moving time domain point source was compared with those by a Havelock source, and satisfactory results were obtained. The panel method based on the time domain source distribution on the ship mean wetted hull surface was used to perform the wave making com- putations tbr mono-hull ships, catamaran and trimaran. Reasonable results were also obtained. Using the numerical method the wave profile simulations of multi-hull ships for a given Froude number were conducted.
