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
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.
文摘目的:探讨替罗非班联合注射用重组人TNK组织型纤溶酶原激活剂(rhTNK-tPA)治疗发病6 h内急性ST段抬高型心肌梗死(STEMI)患者的临床效果。方法:回顾性选取2021年10月~2024年8月期间某院收治的120例行急诊经皮冠状动脉介入术(PCI)的急性STEMI患者的临床资料,依据患者PCI中冠状动脉内用药方案不同分为对照组(n=58,冠状动脉内注射rhTNK-tPA)和观察组(n=62,冠状动脉内注射替罗非班联合rhTNK-tPA)。分析比较两组患者心肌梗死溶栓治疗临床试验(TIMI)血流分级情况、炎症介质[白介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)]、心功能指标[左心室舒张末期内径(LVEDD)、左心室收缩末期内径(LVESD)、左心室射血分数(LVEF)]及治疗后30天内主要心血管不良事件的发生情况。结果:观察组患者给药后8 min TIMI血流3级占比(88.71%)高于对照组(74.14%,P<0.05)。治疗后,两组患者IL-6、TNF-α、LVEDD和LVESD均降低,且观察组低于对照组(P<0.05);LVEF均升高,且观察组高于对照组(P<0.05)。两组患者心血管不良事件总发生率比较无统计学差异(P>0.05)。结论:冠状动脉内应用替罗非班联合rhTNK-tPA可显著提高发病6 h内急性STEMI患者术后再灌注效果,改善心功能指标和炎症介质水平,且不额外增加术后心血管不良事件的发生风险。
