目的总结Top1抑制剂与Tdp1抑制剂整体概况,探究其发展趋势,为后续研究提供参考。方法运用CiteSpace 5.7.R5软件对2012年1月—2022年4月收录在Web of Science(WOS)核心合集数据库中Top1抑制剂与Tdp1抑制剂的相关文献进行作者、机构、被...目的总结Top1抑制剂与Tdp1抑制剂整体概况,探究其发展趋势,为后续研究提供参考。方法运用CiteSpace 5.7.R5软件对2012年1月—2022年4月收录在Web of Science(WOS)核心合集数据库中Top1抑制剂与Tdp1抑制剂的相关文献进行作者、机构、被引期刊、国家、关键词可视化分析。结果共纳入有效文献1186篇,Yves Pommier为发文量最高的作者;美国国家癌症研究所为发文量最高的机构,机构之间具有一定的联系但是合作较为分散,美国研究该领域最全面;Journal of Biological Chemistry为被引率最高的期刊;关键词细胞凋亡、抗肿瘤、抑制剂出现频率高,Top1抑制剂与Tdp1抑制剂研究方向集中于Top1抑制剂、Tdp1抑制剂的发现、合成以及抗肿瘤机制。结论开发更多新型Top1抑制剂、Tdp1抑制剂甚至Top1-Tdp1双靶点抑制剂以进一步提高药物抗肿瘤活性将成为未来研究趋势。展开更多
Our genomic DNA is under constant assault from endogenous and exogenous sources,which needs to be resolved to maintain cellular homeostasis.The eukaryotic DNA repair enzyme Tyrosyl-DNA phosphodiesterase I(Tdp1)catalyz...Our genomic DNA is under constant assault from endogenous and exogenous sources,which needs to be resolved to maintain cellular homeostasis.The eukaryotic DNA repair enzyme Tyrosyl-DNA phosphodiesterase I(Tdp1)catalyzes the hydrolysis of phosphodiester bonds that covalently link adducts to DNA-ends.Tdp1 utilizes two catalytic histidines to resolve a growing list of DNA-adducts.These DNA-adducts can be divided into two groups:small adducts,including oxidized nucleotides,RNA,and non-canonical nucleoside analogs,and large adducts,such as(drug-stabilized)topoisomerase-DNA covalent complexes or failed Schiff base reactions as occur between PARP1 and DNA.Many Tdp1 substrates are generated by chemotherapeutics linking Tdp1 to cancer drug resistance,making a compelling argument to develop small molecules that target Tdp1 as potential novel therapeutic agents.Tdp1’s unique catalytic cycle,which is centered on the formation of Tdp1-DNA covalent reaction intermediate,allows for two principally different targeting strategies:(1)catalytic inhibition of Tdp1 catalysis to prevent Tdp1-mediated repair of DNA-adducts that enhances the effectivity of chemotherapeutics;and(2)poisoning of Tdp1 by stabilization of the Tdp1-DNA covalent reaction intermediate,which would increase the half-life of a potentially toxic DNA-adduct by preventing its resolution,analogous to topoisomerase targeted poisons such as topotecan or etoposide.The catalytic Tdp1 mutant that forms the molecular basis of the autosomal recessive neurodegenerative disease spinocerebellar ataxia with axonal neuropathy best illustrates this concept;however,no small molecules have been reported for this strategy.Herein,we concisely discuss the development of Tdp1 catalytic inhibitors and their results.展开更多
文摘目的总结Top1抑制剂与Tdp1抑制剂整体概况,探究其发展趋势,为后续研究提供参考。方法运用CiteSpace 5.7.R5软件对2012年1月—2022年4月收录在Web of Science(WOS)核心合集数据库中Top1抑制剂与Tdp1抑制剂的相关文献进行作者、机构、被引期刊、国家、关键词可视化分析。结果共纳入有效文献1186篇,Yves Pommier为发文量最高的作者;美国国家癌症研究所为发文量最高的机构,机构之间具有一定的联系但是合作较为分散,美国研究该领域最全面;Journal of Biological Chemistry为被引率最高的期刊;关键词细胞凋亡、抗肿瘤、抑制剂出现频率高,Top1抑制剂与Tdp1抑制剂研究方向集中于Top1抑制剂、Tdp1抑制剂的发现、合成以及抗肿瘤机制。结论开发更多新型Top1抑制剂、Tdp1抑制剂甚至Top1-Tdp1双靶点抑制剂以进一步提高药物抗肿瘤活性将成为未来研究趋势。
基金RCAMvW was in part funded by American Cancer Society UAB ACS-IRG Junior Faculty Development Grant(ACS-IRG-60-001-53)Department of Defense OCRP pilot award W81XWH-15-1-0198the National Institutes of Health Cancer Center Core Support Grant(P30CA013148).
文摘Our genomic DNA is under constant assault from endogenous and exogenous sources,which needs to be resolved to maintain cellular homeostasis.The eukaryotic DNA repair enzyme Tyrosyl-DNA phosphodiesterase I(Tdp1)catalyzes the hydrolysis of phosphodiester bonds that covalently link adducts to DNA-ends.Tdp1 utilizes two catalytic histidines to resolve a growing list of DNA-adducts.These DNA-adducts can be divided into two groups:small adducts,including oxidized nucleotides,RNA,and non-canonical nucleoside analogs,and large adducts,such as(drug-stabilized)topoisomerase-DNA covalent complexes or failed Schiff base reactions as occur between PARP1 and DNA.Many Tdp1 substrates are generated by chemotherapeutics linking Tdp1 to cancer drug resistance,making a compelling argument to develop small molecules that target Tdp1 as potential novel therapeutic agents.Tdp1’s unique catalytic cycle,which is centered on the formation of Tdp1-DNA covalent reaction intermediate,allows for two principally different targeting strategies:(1)catalytic inhibition of Tdp1 catalysis to prevent Tdp1-mediated repair of DNA-adducts that enhances the effectivity of chemotherapeutics;and(2)poisoning of Tdp1 by stabilization of the Tdp1-DNA covalent reaction intermediate,which would increase the half-life of a potentially toxic DNA-adduct by preventing its resolution,analogous to topoisomerase targeted poisons such as topotecan or etoposide.The catalytic Tdp1 mutant that forms the molecular basis of the autosomal recessive neurodegenerative disease spinocerebellar ataxia with axonal neuropathy best illustrates this concept;however,no small molecules have been reported for this strategy.Herein,we concisely discuss the development of Tdp1 catalytic inhibitors and their results.
