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| 1 | A novel TNKS/USP25 inhibitor blocks the Wnt pathway to overcome multi-drug resistance in TNKS-overexpressing colorectal cancer显示文摘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. | Hongrui Zhu Yamin Gao Liyun Liu Mengyu Tao Xiao Lin Yijia Cheng Yaoyao Shen Haitao Xue Li Guan Huimin Zhao Li Liu Shuping Wang Fan Yang Yongjun Zhou Hongze Liao Fan Sun Houwen Lin | 2024 | Acta Pharmaceutica Sinica B2024，14，1： | 0 |
| 2 | Genomic prediction of yield performance among single-cross maize hybrids using a partial diallel cross design显示文摘Genomic prediction(GP)in plant breeding has the potential to predict and identify the best-performing hybrids based on the genotypes of their parental lines.In a GP experiment,34 elite inbred lines were selected to make 285 single-cross hybrids in a partial-diallel cross design.These lines represented a mini-core collection of Chinese maize germplasm and comprised 18 inbred lines from the Stiff Stalk heterotic group and 16 inbred lines from the Non-Stiff Stalk heterotic group.The parents were genotyped by sequencing and the 285 hybrids were phenotyped for nine yield and yield-related traits at two locations in the summer sowing area(SUS)and three locations in the spring sowing area(SPS)in the main maizeproducing regions of China.Multiple GP models were employed to assess the accuracy of trait prediction in the hybrids.By ten-fold cross-validation,the prediction accuracies of yield performance of the hybrids estimated by the genomic best linear unbiased prediction(GBLUP)model in SUS and SPS were 0.51 and 0.46,respectively.The prediction accuracies of the remaining yield-related traits estimated with GBLUP ranged from 0.49 to 0.86 and from 0.53 to 0.89 in SUS and SPS,respectively.When additive,dominance,epistasis effects,genotype-by-environment interaction,and multi-trait effects were incorporated into the prediction model,the prediction accuracy of hybrid yield performance was improved.The ratio of training to testing population and size of training population optimal for yield prediction were determined.Multiple prediction models can improve prediction accuracy in hybrid breeding. | Ping Luo Houwen Wang Zhiyong Ni Ruisi Yang Fei Wang Hongjun Yong Lin Zhang Zhiqiang Zhou Wei Song Mingshun Li Jie Yang Jianfeng Weng Zhaodong Meng Degui Zhang Jienan Han Yong Chen Runze Zhang Liwei Wang Meng Zhao Wenwei Gao Xiaoyu Chen Wenjie Li Zhuanfang Hao Junjie Fu Xuecai Zhang Xinhai Li | 2023 | The Crop Journal2023，11，6： | 0 |
| 3 | Targeting a cryptic allosteric site of SIRT6 with small-molecule inhibitors that inhibit the migration of pancreatic cancer cells显示文摘SIRT6 belongs to the conserved NAD^(+)-dependent deacetylase superfamily and mediates multiple biological and pathological processes.Targeting SIRT6 by allosteric modulators represents a novel direction for therapeutics,which can overcome the selectivity problem caused by the structural similarity of orthosteric sites among deacetylases.Here,developing a reversed allosteric strategy Allo Reverse,we identified a cryptic allosteric site,Pocket Z,which was only induced by the bi-directional allosteric signal triggered upon orthosteric binding of NAD^(+).Based on Pocket Z,we discovered an SIRT6 allosteric inhibitor named JYQ-42.JYQ-42 selectively targets SIRT6 among other histone deacetylases and effectively inhibits SIRT6 deacetylation,with an IC50 of 2.33μmol/L.JYQ-42 significantly suppresses SIRT6-mediated cancer cell migration and pro-inflammatory cytokine production.JYQ-42,to our knowledge,is the most potent and selective allosteric SIRT6 inhibitor.This study provides a novel strategy for allosteric drug design and will help in the challenging development of therapeutic agents that can selectively bind SIRT6. | Qiufen Zhang Yingyi Chen Duan Ni Zhimin Huang Jiacheng Wei Li Feng Jun-Cheng Su Yingqing Wei Shaobo Ning Xiuyan Yang Mingzhu Zhao Yuran Qiu Kun Song Zhengtian Yu Jianrong Xu Xinyi Li Houwen Lin Shaoyong Lu Jian Zhang | 2022 | Acta Pharmaceutica Sinica B2022，12，2： | 0 |
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