Modulating Tankyrases(TNKS),interactions with USP25 to promote TNKS degradation,rather than inhibiting their enzymatic activities,is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway.H...Modulating Tankyrases(TNKS),interactions with USP25 to promote TNKS degradation,rather than inhibiting their enzymatic activities,is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway.Here,we identified UAT-B,a novel neoantimycin analog isolated from Streptomyces conglobatus,as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction(PPI)to overcome multi-drug resistance in colorectal cancer(CRC).The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels,triggering cell apoptosis through modulation of the Wnt/β-catenin pathway.Importantly,UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels,as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts,as well as APC^(min/+)spontaneous CRC models.Collectively,these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment,and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.展开更多
Main observation and conclusion A divergent and novel protocol for the preparation of both pyrido[2,3,4-kl]acridine and pyrido[4,3,2-kl]acridine alkaloids was developed.This method featured the remote palladium-cataly...Main observation and conclusion A divergent and novel protocol for the preparation of both pyrido[2,3,4-kl]acridine and pyrido[4,3,2-kl]acridine alkaloids was developed.This method featured the remote palladium-catalyzed reductive cyclization with Mo(CO)_(6) as reductant.A wide range of substrates including three types of nitro arenes were tolerated and afforded corresponding products in good to excellent yields.展开更多
基金This study was financially supported by the National Key Research and Development Program of China(2022YFC2804100,2021YFF0502400,2022YFC2804300)National Natural Science Foundation of China(82073713,22137006,82104033,82173730,81903499,32070070,82160669)Innovative research team of highlevel local universities in Shanghai(SHSMU-ZDCX20212702,China).We thank Dr.Juncheng Su from Shanghai Jiao-Tong University School of Medicine(Shanghai,China)for providing the LoVo and COLO 320DM cell lines.
文摘Modulating Tankyrases(TNKS),interactions with USP25 to promote TNKS degradation,rather than inhibiting their enzymatic activities,is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway.Here,we identified UAT-B,a novel neoantimycin analog isolated from Streptomyces conglobatus,as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction(PPI)to overcome multi-drug resistance in colorectal cancer(CRC).The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels,triggering cell apoptosis through modulation of the Wnt/β-catenin pathway.Importantly,UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels,as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts,as well as APC^(min/+)spontaneous CRC models.Collectively,these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment,and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.
基金This project is financially supported by the National Key Research and Development Program of China(No.2018YFC0310900)the National Natural Science Foundation of China(Nos.81903499 and 41729002)the Innovative Research Team of High-Level Local Universities in Shanghai(No.SSMU-ZLCX20180702).
文摘Main observation and conclusion A divergent and novel protocol for the preparation of both pyrido[2,3,4-kl]acridine and pyrido[4,3,2-kl]acridine alkaloids was developed.This method featured the remote palladium-catalyzed reductive cyclization with Mo(CO)_(6) as reductant.A wide range of substrates including three types of nitro arenes were tolerated and afforded corresponding products in good to excellent yields.
