For the first time,proteolysis-targeting chimeras(PROTAC)technology was utilized to achieve the isoform-selective degradation of class I phosphoinositide 3-kinases(PI3Ks)in this study.Through screening and optimizatio...For the first time,proteolysis-targeting chimeras(PROTAC)technology was utilized to achieve the isoform-selective degradation of class I phosphoinositide 3-kinases(PI3Ks)in this study.Through screening and optimization,the PROTAC molecule ZM-PI05 was identified as a selective degrader of p110αin multiple breast cancer cells.More importantly,the degrader can down-regulate p85 regulatory subunit simultaneously,thereby inhibiting the non-enzymatic functions of PI3K that are independent on p110catalytic subunits.Therefore,compared with PI3K inhibitor copanlisib,ZM-PI05 displayed the stronger anti-proliferative activity on breast cancer cells.In brief,a selective and efficient PROTAC molecule was developed to induce the degradation of p110αand concurrent reduction of p85 proteins,providing a tool compound for the biological study of PI3K-αby blocking its enzymatic and non-enzymatic functions.展开更多
Heterogeneous materials are inherently dielectric,and charge distribution and transport in such materials involves complex local fields and polarizations that are remarkably sensitive to morphology and the interaction...Heterogeneous materials are inherently dielectric,and charge distribution and transport in such materials involves complex local fields and polarizations that are remarkably sensitive to morphology and the interaction of conduction and permittivity.Trial and error design of such material systems is time consuming and expensive,and often ineffectual.However,heterogeneous materials are essential for energy conversion and storage,and they have become the foundation for major advances in the performance of devices such as batteries,fuel cells,separation membranes,and solar cells.The present paper presents some relationships in support of rational design based on an extensive experimental validation of the concepts and analysis that form a foundation for that design.Salient results include the prediction and confirmation of volume fraction effects(including nondilute mixtures),and the prediction and direct measurement of surface charge effects at internal interfaces as a function of constituent morphology and orientation.展开更多
基金supported by National Key R&D Program of China(Nos.2021YFA1302100,2021YFA1300200,2020YFE0202200)National Natural Science Foundation of China(Nos.82125034,82330115)。
文摘For the first time,proteolysis-targeting chimeras(PROTAC)technology was utilized to achieve the isoform-selective degradation of class I phosphoinositide 3-kinases(PI3Ks)in this study.Through screening and optimization,the PROTAC molecule ZM-PI05 was identified as a selective degrader of p110αin multiple breast cancer cells.More importantly,the degrader can down-regulate p85 regulatory subunit simultaneously,thereby inhibiting the non-enzymatic functions of PI3K that are independent on p110catalytic subunits.Therefore,compared with PI3K inhibitor copanlisib,ZM-PI05 displayed the stronger anti-proliferative activity on breast cancer cells.In brief,a selective and efficient PROTAC molecule was developed to induce the degradation of p110αand concurrent reduction of p85 proteins,providing a tool compound for the biological study of PI3K-αby blocking its enzymatic and non-enzymatic functions.
文摘Heterogeneous materials are inherently dielectric,and charge distribution and transport in such materials involves complex local fields and polarizations that are remarkably sensitive to morphology and the interaction of conduction and permittivity.Trial and error design of such material systems is time consuming and expensive,and often ineffectual.However,heterogeneous materials are essential for energy conversion and storage,and they have become the foundation for major advances in the performance of devices such as batteries,fuel cells,separation membranes,and solar cells.The present paper presents some relationships in support of rational design based on an extensive experimental validation of the concepts and analysis that form a foundation for that design.Salient results include the prediction and confirmation of volume fraction effects(including nondilute mixtures),and the prediction and direct measurement of surface charge effects at internal interfaces as a function of constituent morphology and orientation.
