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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 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.

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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Targeting DNA repair pathways to overcome cancer drug resistance

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cancer Drug Resistance 2021年第4期4卷 837-841页

作者： Robert C.A.M.van waardenburg Eddy S.Yang department of Pharmacology and Toxicology University of Alabama at BirminghamBirminghamAL 35233USA department of Radiation Oncology University of Alabama at BirminghamBirminghamAL 35233USA O’Neal Comprehensive cancer center University of Alabama at BirminghamBirminghamAL 35233USA

DNA damage response and DNA repair pathways are evolutionarily conserved from prokaryotes to eukaryotes to protect the host from genomic instability.Dysregulation of proteins involved in these pathways in mammalian cells increases genomic alterations leading to genomic instability,a well-established hallmark of cancer^([1,2]).However,our understanding of the signaling pathways to repair DNA damage in cancers has grown exponentially over the last decades.

关键词： damage alterations cancer

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Targeting DNA topoisomerases: past & future

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cancer Drug Resistance 2021年第4期4卷 758-761页

作者： william H.Gmeiner Robert C.A.Mvan waardenburg department of cancer Biology wake Forest School of Medicine Medical Center BlvdWinston-SalemNC 27157USA department of Pharmacology and Toxicology University of Alabama at BirminghamBirminghamAL 35294-0019USA

Aggressive malignancies are characterized by relatively uncontrolled cell proliferation making them especially reliant on topoisomerase enzymes to enable high rates of DNA replication and transcription.DNA topoisomerases resolve topological problems associated with DNA replication and other essential cellular processes involving DNA,such as transcription and recombination^([1]).As such,they are important targets for anti-cancer therapeutics.Further,understanding of topoisomerase biology is important for unraveling the mechanistic basis for resistance to many widely used anti-cancer drugs,such as doxorubicin,etoposide,and topotecan,for which DNA topoisomerases are established targets.Interestingly,several drugs that are not considered to directly target topoisomerase enzymes,such as the nucleoside analogs 5-FU and AraC,and those in development such as the polymeric fluoropyrimidine CF10^([2]),also affect the function of topoisomerases.

关键词： analogs topological enable

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