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Targeting Tyrosyl-dna phosphodiesterase I to enhance toxicity of phosphodiester linked dna-adducts

Cancer Drug Resistance 2019年第4期2卷 1153-1163页

作者： Evan J.Brettrager Robert C.A.M.van Waardenburg Department of Pharmacology and Toxicology University of Alabama at BirminghamBirminghamAL 35294-0019USA

Our genomic dna is under constant assault from endogenous and exogenous sources,which needs to be resolved to maintain cellular *** eukaryotic dna repair enzyme Tyrosyl-dna phosphodiesterase I(Tdp1)catalyzes the hydrolysis of phosphodiester bonds that covalently link adducts to ***1 utilizes two catalytic histidines to resolve a growing list of *** 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 *** 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 ***1’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 *** 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 ***,we concisely discuss the development of Tdp1 catalytic inhibitors and their results.

关键词： Tdp1 small molecules dna topoisomerases Camptothecins oxidative dna damage dna adducts Etoposide chain terminating nucleotides/nucleoside analogs dna metabolism drug development

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