Cyclin-dependent kinases(CDKs) have become potential targets for treating various diseases, especially cancer. Compound i CDK9 is an excellent and selective CDK9 inhibitor, but its major limitation is the potential to...Cyclin-dependent kinases(CDKs) have become potential targets for treating various diseases, especially cancer. Compound i CDK9 is an excellent and selective CDK9 inhibitor, but its major limitation is the potential toxicity and poor understanding of the underlying mechanism. The PROTAC(proteolysis targeting chimera) degraders of bioactive molecules can significantly induce in vitro and in vivo degradation of their target protein with high selectivity and effectively reduce the dose-limiting toxicity of small molecule drugs. Therefore, we designed and synthesized the bifunctional PROTAC molecules of i CDK9, being used for identifying its previously unknown target and revealing the underlying pharmacological mechanism.The PROTAC bifunctional molecule CD-5 could selectively and significantly degrade CDK9 with low cell toxicity. Therefore, we selected CD-5 as a chemical prober in the SILAC quantitative proteomic analysis, which disclosed that CD-5 could enormously lessen the lysine acetyltransferase KAT6A. Furthermore,KAT6A degradation induced by CD-5 repressed the levels of H3K14Ac and H3K23Ac. Lastly, the streptavidin immunoprecipitation(IP) assay confirmed a direct interaction between KAT6A and i CDK9. Collectively, our results uncover that KAT6A is a potential non-kinase target of i CDK9. Notably, this study also demonstrates that the PROTAC-SILAC strategy is an alternative approach for cellular target identification of bioactive molecules.展开更多
Polymer-textile liner composites have potential applications in aerospace applications for reducing the abrasion damage of moving parts during operation owing to their self-lubrication,light weight,and high loading ca...Polymer-textile liner composites have potential applications in aerospace applications for reducing the abrasion damage of moving parts during operation owing to their self-lubrication,light weight,and high loading capacity.Herein,Au nanoparticles(AuNPs)are successfully loaded into the lumen of halloysite nanotubes(HNTs)to construct an HNTs‒Au peasecod core‒shell nanosystem to optimize the wear resistance of phenolic resin-based poly(p-phenylene benzobisoxazole)(PBO)/polytetrafluoroethylene(PTFE)textile composites.Transmission electron microscope(TEM)characterization reveals that the AuNPs are well-dispersed inside the HNTs,with an average diameter of 6‒9 nm.The anti-wear performance of the HNTs and Au-reinforced PBO/PTFE composites is evaluated using a pin-on-disk friction tester at 100 MPa.Evidently,the addition of HNTs‒Au induces a 27.9%decrease in the wear rate of the composites.Possible anti-wear mechanisms are proposed based on the analyzed results of the worn surface morphology and the cross-section of the tribofilm obtained by focused ion beam transmission electron microscopy.展开更多
基金supported by grants from the National Key R&D Program of China (Nos. 2018YFA0107303 and 2020YFA0908100)the National Natural Science Foundation of China (Nos. 81773600and 82102746)+1 种基金the China Postdoctoral Science Foundation (No.2021M690095)the Fundamental Research Funds for the Central Universities (No. 20720180051)。
文摘Cyclin-dependent kinases(CDKs) have become potential targets for treating various diseases, especially cancer. Compound i CDK9 is an excellent and selective CDK9 inhibitor, but its major limitation is the potential toxicity and poor understanding of the underlying mechanism. The PROTAC(proteolysis targeting chimera) degraders of bioactive molecules can significantly induce in vitro and in vivo degradation of their target protein with high selectivity and effectively reduce the dose-limiting toxicity of small molecule drugs. Therefore, we designed and synthesized the bifunctional PROTAC molecules of i CDK9, being used for identifying its previously unknown target and revealing the underlying pharmacological mechanism.The PROTAC bifunctional molecule CD-5 could selectively and significantly degrade CDK9 with low cell toxicity. Therefore, we selected CD-5 as a chemical prober in the SILAC quantitative proteomic analysis, which disclosed that CD-5 could enormously lessen the lysine acetyltransferase KAT6A. Furthermore,KAT6A degradation induced by CD-5 repressed the levels of H3K14Ac and H3K23Ac. Lastly, the streptavidin immunoprecipitation(IP) assay confirmed a direct interaction between KAT6A and i CDK9. Collectively, our results uncover that KAT6A is a potential non-kinase target of i CDK9. Notably, this study also demonstrates that the PROTAC-SILAC strategy is an alternative approach for cellular target identification of bioactive molecules.
基金The authors acknowledge the financial support of the National Natural Science Foundation of China(Nos.52075523 and 52005487).
文摘Polymer-textile liner composites have potential applications in aerospace applications for reducing the abrasion damage of moving parts during operation owing to their self-lubrication,light weight,and high loading capacity.Herein,Au nanoparticles(AuNPs)are successfully loaded into the lumen of halloysite nanotubes(HNTs)to construct an HNTs‒Au peasecod core‒shell nanosystem to optimize the wear resistance of phenolic resin-based poly(p-phenylene benzobisoxazole)(PBO)/polytetrafluoroethylene(PTFE)textile composites.Transmission electron microscope(TEM)characterization reveals that the AuNPs are well-dispersed inside the HNTs,with an average diameter of 6‒9 nm.The anti-wear performance of the HNTs and Au-reinforced PBO/PTFE composites is evaluated using a pin-on-disk friction tester at 100 MPa.Evidently,the addition of HNTs‒Au induces a 27.9%decrease in the wear rate of the composites.Possible anti-wear mechanisms are proposed based on the analyzed results of the worn surface morphology and the cross-section of the tribofilm obtained by focused ion beam transmission electron microscopy.
