Catalytic Cleavage of Disulfide Bonds in Small Molecules and Linkers of Antibody-Drug Conjugates.
Identifieur interne : 000189 ( Main/Exploration ); précédent : 000188; suivant : 000190Catalytic Cleavage of Disulfide Bonds in Small Molecules and Linkers of Antibody-Drug Conjugates.
Auteurs : Donglu Zhang [Oman] ; Aimee Fourie-O'Donohue [États-Unis] ; Peter S. Dragovich [États-Unis] ; Thomas H. Pillow [États-Unis] ; Jack D. Sadowsky [États-Unis] ; Katherine R. Kozak [États-Unis] ; Robert T. Cass [États-Unis] ; Liling Liu [États-Unis] ; Yuzhong Deng [États-Unis] ; Yichin Liu [États-Unis] ; Cornelis E C A. Hop [États-Unis] ; S Cyrus Khojasteh [Oman]Source :
- Drug metabolism and disposition: the biological fate of chemicals [ 1521-009X ] ; 2019.
Descripteurs français
- KwdFr :
- Animaux (MeSH), Benzodiazépines (composition chimique), Benzodiazépines (métabolisme), Disulfures (composition chimique), Disulfures (métabolisme), Femelle (MeSH), Glutarédoxines (métabolisme), Humains (MeSH), Immunoconjugués (composition chimique), Immunoconjugués (pharmacocinétique), Mâle (MeSH), Protéines recombinantes (métabolisme), Pyrroles (composition chimique), Pyrroles (métabolisme), Rats (MeSH), Thioredoxin-disulfide reductase (métabolisme), Thiorédoxines (métabolisme).
- MESH :
- composition chimique : Benzodiazépines, Disulfures, Immunoconjugués, Pyrroles.
- métabolisme : Benzodiazépines, Disulfures, Glutarédoxines, Protéines recombinantes, Pyrroles, Thioredoxin-disulfide reductase, Thiorédoxines.
- pharmacocinétique : Immunoconjugués.
- Animaux, Femelle, Humains, Mâle, Rats.
English descriptors
- KwdEn :
- Animals (MeSH), Benzodiazepines (chemistry), Benzodiazepines (metabolism), Disulfides (chemistry), Disulfides (metabolism), Female (MeSH), Glutaredoxins (metabolism), Humans (MeSH), Immunoconjugates (chemistry), Immunoconjugates (pharmacokinetics), Male (MeSH), Pyrroles (chemistry), Pyrroles (metabolism), Rats (MeSH), Recombinant Proteins (metabolism), Thioredoxin-Disulfide Reductase (metabolism), Thioredoxins (metabolism).
- MESH :
- chemical , chemistry : Benzodiazepines, Disulfides, Immunoconjugates, Pyrroles.
- chemical , metabolism : Benzodiazepines, Disulfides, Glutaredoxins, Pyrroles, Recombinant Proteins, Thioredoxin-Disulfide Reductase, Thioredoxins.
- chemical , pharmacokinetics : Immunoconjugates.
- Animals, Female, Humans, Male, Rats.
Abstract
In cells, catalytic disulfide cleavage is an essential mechanism in protein folding and synthesis. However, detailed enzymatic catalytic mechanism relating cleavage of disulfide bonds in xenobiotics is not well understood. This study reports an enzymatic mechanism of cleavage of disulfide bonds in xenobiotic small molecules and antibody conjugate (ADC) linkers. The chemically stable disulfide bonds in substituted disulfide-containing pyrrolobenzodiazepine (PBD, pyrrolo[2,1-c][1,4]benzodiazepine) monomer prodrugs in presence of glutathione or cysteine were found to be unstable in incubations in whole blood of humans and rats. It was shown the enzymes involved were thioredoxin (TRX) and glutaredoxin (GRX). For a diverse set of drug-linker conjugates, we determined that TRX in the presence of TRX-reductase and NADPH generated the cleaved products that are consistent with catalytic disulfide cleavage and linker immolation. GRX was less rigorously studied; in the set of compounds studied, its role in the catalytic cleavage was also confirmed. Collectively, these in vitro experiments demonstrate that TRX as well as GRX can catalyze the cleavage of disulfide bonds in both small molecules and linkers of ADCs.
DOI: 10.1124/dmd.118.086132
PubMed: 31085544
Affiliations:
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Hop</name><affiliation wicri:level="2"><nlm:affiliation>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco, California.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco</wicri:cityArea></affiliation></author><author><name sortKey="Khojasteh, S Cyrus" sort="Khojasteh, S Cyrus" uniqKey="Khojasteh S" first="S Cyrus" last="Khojasteh">S Cyrus Khojasteh</name><affiliation wicri:level="1"><nlm:affiliation>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco, California khojasteh.cyrus@gene.com.</nlm:affiliation><country wicri:rule="url">Oman</country><wicri:regionArea>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco</wicri:regionArea><wicri:noRegion>South San Francisco</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2019">2019</date><idno type="RBID">pubmed:31085544</idno><idno type="pmid">31085544</idno><idno type="doi">10.1124/dmd.118.086132</idno><idno type="wicri:Area/Main/Corpus">000142</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000142</idno><idno type="wicri:Area/Main/Curation">000142</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000142</idno><idno type="wicri:Area/Main/Exploration">000142</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Catalytic Cleavage of Disulfide Bonds in Small Molecules and Linkers of Antibody-Drug Conjugates.</title><author><name sortKey="Zhang, Donglu" sort="Zhang, Donglu" uniqKey="Zhang D" first="Donglu" last="Zhang">Donglu Zhang</name><affiliation wicri:level="1"><nlm:affiliation>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco, California zhang.donglu@gene.com.</nlm:affiliation><country wicri:rule="url">Oman</country><wicri:regionArea>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco</wicri:regionArea><wicri:noRegion>South San Francisco</wicri:noRegion></affiliation></author><author><name sortKey="Fourie O Donohue, Aimee" sort="Fourie O Donohue, Aimee" uniqKey="Fourie O Donohue A" first="Aimee" last="Fourie-O'Donohue">Aimee Fourie-O'Donohue</name><affiliation wicri:level="2"><nlm:affiliation>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco, California.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco</wicri:cityArea></affiliation></author><author><name sortKey="Dragovich, Peter S" sort="Dragovich, Peter S" uniqKey="Dragovich P" first="Peter S" last="Dragovich">Peter S. Dragovich</name><affiliation wicri:level="2"><nlm:affiliation>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco, California.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco</wicri:cityArea></affiliation></author><author><name sortKey="Pillow, Thomas H" sort="Pillow, Thomas H" uniqKey="Pillow T" first="Thomas H" last="Pillow">Thomas H. Pillow</name><affiliation wicri:level="2"><nlm:affiliation>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco, California.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco</wicri:cityArea></affiliation></author><author><name sortKey="Sadowsky, Jack D" sort="Sadowsky, Jack D" uniqKey="Sadowsky J" first="Jack D" last="Sadowsky">Jack D. Sadowsky</name><affiliation wicri:level="2"><nlm:affiliation>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco, California.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco</wicri:cityArea></affiliation></author><author><name sortKey="Kozak, Katherine R" sort="Kozak, Katherine R" uniqKey="Kozak K" first="Katherine R" last="Kozak">Katherine R. Kozak</name><affiliation wicri:level="2"><nlm:affiliation>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco, California.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco</wicri:cityArea></affiliation></author><author><name sortKey="Cass, Robert T" sort="Cass, Robert T" uniqKey="Cass R" first="Robert T" last="Cass">Robert T. Cass</name><affiliation wicri:level="2"><nlm:affiliation>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco, California.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco</wicri:cityArea></affiliation></author><author><name sortKey="Liu, Liling" sort="Liu, Liling" uniqKey="Liu L" first="Liling" last="Liu">Liling Liu</name><affiliation wicri:level="2"><nlm:affiliation>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco, California.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco</wicri:cityArea></affiliation></author><author><name sortKey="Deng, Yuzhong" sort="Deng, Yuzhong" uniqKey="Deng Y" first="Yuzhong" last="Deng">Yuzhong Deng</name><affiliation wicri:level="2"><nlm:affiliation>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco, California.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco</wicri:cityArea></affiliation></author><author><name sortKey="Liu, Yichin" sort="Liu, Yichin" uniqKey="Liu Y" first="Yichin" last="Liu">Yichin Liu</name><affiliation wicri:level="2"><nlm:affiliation>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco, California.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco</wicri:cityArea></affiliation></author><author><name sortKey="Hop, Cornelis E C A" sort="Hop, Cornelis E C A" uniqKey="Hop C" first="Cornelis E C A" last="Hop">Cornelis E C A. Hop</name><affiliation wicri:level="2"><nlm:affiliation>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco, California.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco</wicri:cityArea></affiliation></author><author><name sortKey="Khojasteh, S Cyrus" sort="Khojasteh, S Cyrus" uniqKey="Khojasteh S" first="S Cyrus" last="Khojasteh">S Cyrus Khojasteh</name><affiliation wicri:level="1"><nlm:affiliation>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco, California khojasteh.cyrus@gene.com.</nlm:affiliation><country wicri:rule="url">Oman</country><wicri:regionArea>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco</wicri:regionArea><wicri:noRegion>South San Francisco</wicri:noRegion></affiliation></author></analytic><series><title level="j">Drug metabolism and disposition: the biological fate of chemicals</title><idno type="eISSN">1521-009X</idno><imprint><date when="2019" type="published">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals (MeSH)</term><term>Benzodiazepines (chemistry)</term><term>Benzodiazepines (metabolism)</term><term>Disulfides (chemistry)</term><term>Disulfides (metabolism)</term><term>Female (MeSH)</term><term>Glutaredoxins (metabolism)</term><term>Humans (MeSH)</term><term>Immunoconjugates (chemistry)</term><term>Immunoconjugates (pharmacokinetics)</term><term>Male (MeSH)</term><term>Pyrroles (chemistry)</term><term>Pyrroles (metabolism)</term><term>Rats (MeSH)</term><term>Recombinant Proteins (metabolism)</term><term>Thioredoxin-Disulfide Reductase (metabolism)</term><term>Thioredoxins (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux (MeSH)</term><term>Benzodiazépines (composition chimique)</term><term>Benzodiazépines (métabolisme)</term><term>Disulfures (composition chimique)</term><term>Disulfures (métabolisme)</term><term>Femelle (MeSH)</term><term>Glutarédoxines (métabolisme)</term><term>Humains (MeSH)</term><term>Immunoconjugués (composition chimique)</term><term>Immunoconjugués (pharmacocinétique)</term><term>Mâle (MeSH)</term><term>Protéines recombinantes (métabolisme)</term><term>Pyrroles (composition chimique)</term><term>Pyrroles (métabolisme)</term><term>Rats (MeSH)</term><term>Thioredoxin-disulfide reductase (métabolisme)</term><term>Thiorédoxines (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Benzodiazepines</term><term>Disulfides</term><term>Immunoconjugates</term><term>Pyrroles</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Benzodiazepines</term><term>Disulfides</term><term>Glutaredoxins</term><term>Pyrroles</term><term>Recombinant Proteins</term><term>Thioredoxin-Disulfide Reductase</term><term>Thioredoxins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacokinetics" xml:lang="en"><term>Immunoconjugates</term></keywords><keywords scheme="MESH" qualifier="composition chimique" xml:lang="fr"><term>Benzodiazépines</term><term>Disulfures</term><term>Immunoconjugués</term><term>Pyrroles</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Benzodiazépines</term><term>Disulfures</term><term>Glutarédoxines</term><term>Protéines recombinantes</term><term>Pyrroles</term><term>Thioredoxin-disulfide reductase</term><term>Thiorédoxines</term></keywords><keywords scheme="MESH" qualifier="pharmacocinétique" xml:lang="fr"><term>Immunoconjugués</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Female</term><term>Humans</term><term>Male</term><term>Rats</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Femelle</term><term>Humains</term><term>Mâle</term><term>Rats</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">In cells, catalytic disulfide cleavage is an essential mechanism in protein folding and synthesis. However, detailed enzymatic catalytic mechanism relating cleavage of disulfide bonds in xenobiotics is not well understood. This study reports an enzymatic mechanism of cleavage of disulfide bonds in xenobiotic small molecules and antibody conjugate (ADC) linkers. The chemically stable disulfide bonds in substituted disulfide-containing pyrrolobenzodiazepine (PBD, pyrrolo[2,1-c][1,4]benzodiazepine) monomer prodrugs in presence of glutathione or cysteine were found to be unstable in incubations in whole blood of humans and rats. It was shown the enzymes involved were thioredoxin (TRX) and glutaredoxin (GRX). For a diverse set of drug-linker conjugates, we determined that TRX in the presence of TRX-reductase and NADPH generated the cleaved products that are consistent with catalytic disulfide cleavage and linker immolation. GRX was less rigorously studied; in the set of compounds studied, its role in the catalytic cleavage was also confirmed. Collectively, these in vitro experiments demonstrate that TRX as well as GRX can catalyze the cleavage of disulfide bonds in both small molecules and linkers of ADCs.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">31085544</PMID><DateCompleted><Year>2020</Year><Month>06</Month><Day>01</Day></DateCompleted><DateRevised><Year>2020</Year><Month>06</Month><Day>01</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1521-009X</ISSN><JournalIssue CitedMedium="Internet"><Volume>47</Volume><Issue>10</Issue><PubDate><Year>2019</Year><Month>10</Month></PubDate></JournalIssue><Title>Drug metabolism and disposition: the biological fate of chemicals</Title><ISOAbbreviation>Drug Metab Dispos</ISOAbbreviation></Journal><ArticleTitle>Catalytic Cleavage of Disulfide Bonds in Small Molecules and Linkers of Antibody-Drug Conjugates.</ArticleTitle><Pagination><MedlinePgn>1156-1163</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1124/dmd.118.086132</ELocationID><Abstract><AbstractText>In cells, catalytic disulfide cleavage is an essential mechanism in protein folding and synthesis. However, detailed enzymatic catalytic mechanism relating cleavage of disulfide bonds in xenobiotics is not well understood. This study reports an enzymatic mechanism of cleavage of disulfide bonds in xenobiotic small molecules and antibody conjugate (ADC) linkers. The chemically stable disulfide bonds in substituted disulfide-containing pyrrolobenzodiazepine (PBD, pyrrolo[2,1-c][1,4]benzodiazepine) monomer prodrugs in presence of glutathione or cysteine were found to be unstable in incubations in whole blood of humans and rats. It was shown the enzymes involved were thioredoxin (TRX) and glutaredoxin (GRX). For a diverse set of drug-linker conjugates, we determined that TRX in the presence of TRX-reductase and NADPH generated the cleaved products that are consistent with catalytic disulfide cleavage and linker immolation. GRX was less rigorously studied; in the set of compounds studied, its role in the catalytic cleavage was also confirmed. Collectively, these in vitro experiments demonstrate that TRX as well as GRX can catalyze the cleavage of disulfide bonds in both small molecules and linkers of ADCs.</AbstractText><CopyrightInformation>Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Zhang</LastName><ForeName>Donglu</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco, California zhang.donglu@gene.com.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fourie-O'Donohue</LastName><ForeName>Aimee</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco, California.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dragovich</LastName><ForeName>Peter S</ForeName><Initials>PS</Initials><AffiliationInfo><Affiliation>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco, California.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Pillow</LastName><ForeName>Thomas H</ForeName><Initials>TH</Initials><AffiliationInfo><Affiliation>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco, California.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sadowsky</LastName><ForeName>Jack D</ForeName><Initials>JD</Initials><AffiliationInfo><Affiliation>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco, California.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kozak</LastName><ForeName>Katherine R</ForeName><Initials>KR</Initials><AffiliationInfo><Affiliation>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco, California.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cass</LastName><ForeName>Robert T</ForeName><Initials>RT</Initials><AffiliationInfo><Affiliation>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco, California.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Liu</LastName><ForeName>Liling</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco, California.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Deng</LastName><ForeName>Yuzhong</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco, California.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Liu</LastName><ForeName>Yichin</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco, California.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hop</LastName><ForeName>Cornelis E C A</ForeName><Initials>CECA</Initials><AffiliationInfo><Affiliation>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco, California.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Khojasteh</LastName><ForeName>S Cyrus</ForeName><Initials>SC</Initials><AffiliationInfo><Affiliation>Drug Metabolism & Pharmacokinetics (D.Z., R.T.C., L.L., Y.D., C.E.C.A.H., S.C.K.), Biochemical and Cellular Pharmacology (A.F.-O., K.R.K., Y.L.), Discovery Chemistry (P.S.D., T.H.P.), and Protein Chemistry (J.D.S.), Genentech, Inc., South San Francisco, California khojasteh.cyrus@gene.com.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2019</Year><Month>05</Month><Day>13</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Drug Metab Dispos</MedlineTA><NlmUniqueID>9421550</NlmUniqueID><ISSNLinking>0090-9556</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D004220">Disulfides</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C516005">GLRX protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D054477">Glutaredoxins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D018796">Immunoconjugates</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011758">Pyrroles</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011994">Recombinant Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C491203">TXN protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C495697">Txn1 protein, rat</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C438462">pyrrolo(2,1-c)(1,4)benzodiazepine</NameOfSubstance></Chemical><Chemical><RegistryNumber>12794-10-4</RegistryNumber><NameOfSubstance UI="D001569">Benzodiazepines</NameOfSubstance></Chemical><Chemical><RegistryNumber>52500-60-4</RegistryNumber><NameOfSubstance UI="D013879">Thioredoxins</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 1.8.1.9</RegistryNumber><NameOfSubstance UI="D013880">Thioredoxin-Disulfide Reductase</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D001569" MajorTopicYN="N">Benzodiazepines</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004220" MajorTopicYN="N">Disulfides</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D054477" MajorTopicYN="N">Glutaredoxins</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018796" MajorTopicYN="N">Immunoconjugates</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000493" MajorTopicYN="Y">pharmacokinetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011758" MajorTopicYN="N">Pyrroles</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051381" MajorTopicYN="N">Rats</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011994" MajorTopicYN="N">Recombinant Proteins</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013880" MajorTopicYN="N">Thioredoxin-Disulfide Reductase</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013879" MajorTopicYN="N">Thioredoxins</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2018</Year><Month>12</Month><Day>24</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2019</Year><Month>05</Month><Day>07</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2019</Year><Month>5</Month><Day>16</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2020</Year><Month>6</Month><Day>2</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2019</Year><Month>5</Month><Day>16</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">31085544</ArticleId><ArticleId IdType="pii">dmd.118.086132</ArticleId><ArticleId IdType="doi">10.1124/dmd.118.086132</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Oman</li><li>États-Unis</li></country><region><li>Californie</li></region></list><tree><country name="Oman"><noRegion><name sortKey="Zhang, Donglu" sort="Zhang, Donglu" uniqKey="Zhang D" first="Donglu" last="Zhang">Donglu Zhang</name></noRegion><name sortKey="Khojasteh, S Cyrus" sort="Khojasteh, S Cyrus" uniqKey="Khojasteh S" first="S Cyrus" last="Khojasteh">S Cyrus Khojasteh</name></country><country name="États-Unis"><region name="Californie"><name sortKey="Fourie O Donohue, Aimee" sort="Fourie O Donohue, Aimee" uniqKey="Fourie O Donohue A" first="Aimee" last="Fourie-O'Donohue">Aimee Fourie-O'Donohue</name></region><name sortKey="Cass, Robert T" sort="Cass, Robert T" uniqKey="Cass R" first="Robert T" last="Cass">Robert T. Cass</name><name sortKey="Deng, Yuzhong" sort="Deng, Yuzhong" uniqKey="Deng Y" first="Yuzhong" last="Deng">Yuzhong Deng</name><name sortKey="Dragovich, Peter S" sort="Dragovich, Peter S" uniqKey="Dragovich P" first="Peter S" last="Dragovich">Peter S. Dragovich</name><name sortKey="Hop, Cornelis E C A" sort="Hop, Cornelis E C A" uniqKey="Hop C" first="Cornelis E C A" last="Hop">Cornelis E C A. Hop</name><name sortKey="Kozak, Katherine R" sort="Kozak, Katherine R" uniqKey="Kozak K" first="Katherine R" last="Kozak">Katherine R. Kozak</name><name sortKey="Liu, Liling" sort="Liu, Liling" uniqKey="Liu L" first="Liling" last="Liu">Liling Liu</name><name sortKey="Liu, Yichin" sort="Liu, Yichin" uniqKey="Liu Y" first="Yichin" last="Liu">Yichin Liu</name><name sortKey="Pillow, Thomas H" sort="Pillow, Thomas H" uniqKey="Pillow T" first="Thomas H" last="Pillow">Thomas H. Pillow</name><name sortKey="Sadowsky, Jack D" sort="Sadowsky, Jack D" uniqKey="Sadowsky J" first="Jack D" last="Sadowsky">Jack D. Sadowsky</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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