RapamycinFungusV1, Main, Exploration, bibRecord, 000539

Neolymphostin A Is a Covalent Phosphoinositide 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Dual Inhibitor That Employs an Unusual Electrophilic Vinylogous Ester.

Identifieur interne : 000539 ( Main/Exploration ); précédent : 000538; suivant : 000540

Neolymphostin A Is a Covalent Phosphoinositide 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Dual Inhibitor That Employs an Unusual Electrophilic Vinylogous Ester.

Auteurs : Gabriel Castro-Falc N [États-Unis] ; Grant S. Seiler [États-Unis] ; Özlem Demir [États-Unis] ; Manoj K. Rathinaswamy [Canada] ; David Hamelin [Canada] ; Reece M. Hoffmann [Canada] ; Stefanie L. Makowski [États-Unis] ; Anne-Catrin Letzel [États-Unis] ; Seth J. Field [États-Unis] ; John E. Burke [Canada] ; Rommie E. Amaro [États-Unis] ; Chambers C. Hughes [États-Unis]

Source :

Journal of medicinal chemistry [ 1520-4804 ] ; 2018.

RBID : pubmed:30380865

Descripteurs français

KwdFr :
- Antienzymes (composition chimique), Antienzymes (métabolisme), Antienzymes (pharmacologie), Conformation des protéines (MeSH), Esters (composition chimique), Phosphatidylinositol 3-kinases (composition chimique), Phosphatidylinositol 3-kinases (métabolisme), Quinoléines (composition chimique), Quinoléines (métabolisme), Quinoléines (pharmacologie), Simulation de docking moléculaire (MeSH), Sérine-thréonine kinases TOR (antagonistes et inhibiteurs).
MESH :
- antagonistes et inhibiteurs : Sérine-thréonine kinases TOR.
- composition chimique : Antienzymes, Esters, Phosphatidylinositol 3-kinases, Quinoléines.
- métabolisme : Antienzymes, Phosphatidylinositol 3-kinases, Quinoléines.
- pharmacologie : Antienzymes, Quinoléines.
- Conformation des protéines, Simulation de docking moléculaire.

English descriptors

KwdEn :
- Enzyme Inhibitors (chemistry), Enzyme Inhibitors (metabolism), Enzyme Inhibitors (pharmacology), Esters (chemistry), Molecular Docking Simulation (MeSH), Phosphatidylinositol 3-Kinases (chemistry), Phosphatidylinositol 3-Kinases (metabolism), Phosphoinositide-3 Kinase Inhibitors (MeSH), Protein Conformation (MeSH), Quinolines (chemistry), Quinolines (metabolism), Quinolines (pharmacology), TOR Serine-Threonine Kinases (antagonists & inhibitors).
MESH :
- chemical , antagonists & inhibitors : TOR Serine-Threonine Kinases.
- chemical , chemistry : Enzyme Inhibitors, Esters, Quinolines.
- chemical , metabolism : Enzyme Inhibitors, Quinolines.
- chemical , pharmacology : Enzyme Inhibitors, Quinolines.
- chemistry : Phosphatidylinositol 3-Kinases.
- metabolism : Phosphatidylinositol 3-Kinases.
- Molecular Docking Simulation, Phosphoinositide-3 Kinase Inhibitors, Protein Conformation.

Abstract

Using a novel chemistry-based assay for identifying electrophilic natural products in unprocessed extracts, we identified the PI3-kinase/mTOR dual inhibitor neolymphostin A from Salinispora arenicola CNY-486. The method further showed that the vinylogous ester substituent on the neolymphostin core was the exact site for enzyme conjugation. Tandem MS/MS experiments on PI3Kα treated with the inhibitor revealed that neolymphostin covalently modified Lys802 with a shift in mass of +306 amu, corresponding to addition of the inhibitor and elimination of methanol. The binding pose of the inhibitor bound to PI3Kα was modeled, and hydrogen-deuterium exchange mass spectrometry experiments supported this model. Against a panel of kinases, neolymphostin showed good selectivity for PI3-kinase and mTOR. In addition, the natural product blocked AKT phosphorylation in live cells with an IC₅₀ of ∼3 nM. Taken together, neolymphostin is the first reported example of a covalent kinase inhibitor from the bacterial domain of life.

DOI: 10.1021/acs.jmedchem.8b00975
PubMed: 30380865
PubMed Central: PMC6688905

Affiliations:

Canada, États-Unis

Links toward previous steps (curation, corpus...)

to stream Main, to step Corpus: 000416
to stream Main, to step Curation: 000416

Le document en format XML

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<sourceDesc><biblStruct><analytic><title xml:lang="en">Neolymphostin A Is a Covalent Phosphoinositide 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Dual Inhibitor That Employs an Unusual Electrophilic Vinylogous Ester.</title>
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<author><name sortKey="Makowski, Stefanie L" sort="Makowski, Stefanie L" uniqKey="Makowski S" first="Stefanie L" last="Makowski">Stefanie L. Makowski</name>
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<wicri:regionArea>Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography , University of California, San Diego , La Jolla , California 92093 </wicri:regionArea>
<wicri:noRegion>California 92093 </wicri:noRegion>
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<author><name sortKey="Field, Seth J" sort="Field, Seth J" uniqKey="Field S" first="Seth J" last="Field">Seth J. Field</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 </wicri:regionArea>
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<author><name sortKey="Hughes, Chambers C" sort="Hughes, Chambers C" uniqKey="Hughes C" first="Chambers C" last="Hughes">Chambers C. Hughes</name>
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<term>Enzyme Inhibitors (metabolism)</term>
<term>Enzyme Inhibitors (pharmacology)</term>
<term>Esters (chemistry)</term>
<term>Molecular Docking Simulation (MeSH)</term>
<term>Phosphatidylinositol 3-Kinases (chemistry)</term>
<term>Phosphatidylinositol 3-Kinases (metabolism)</term>
<term>Phosphoinositide-3 Kinase Inhibitors (MeSH)</term>
<term>Protein Conformation (MeSH)</term>
<term>Quinolines (chemistry)</term>
<term>Quinolines (metabolism)</term>
<term>Quinolines (pharmacology)</term>
<term>TOR Serine-Threonine Kinases (antagonists & inhibitors)</term>
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<term>Antienzymes (métabolisme)</term>
<term>Antienzymes (pharmacologie)</term>
<term>Conformation des protéines (MeSH)</term>
<term>Esters (composition chimique)</term>
<term>Phosphatidylinositol 3-kinases (composition chimique)</term>
<term>Phosphatidylinositol 3-kinases (métabolisme)</term>
<term>Quinoléines (composition chimique)</term>
<term>Quinoléines (métabolisme)</term>
<term>Quinoléines (pharmacologie)</term>
<term>Simulation de docking moléculaire (MeSH)</term>
<term>Sérine-thréonine kinases TOR (antagonistes et inhibiteurs)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>TOR Serine-Threonine Kinases</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Enzyme Inhibitors</term>
<term>Esters</term>
<term>Quinolines</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Enzyme Inhibitors</term>
<term>Quinolines</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Enzyme Inhibitors</term>
<term>Quinolines</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Sérine-thréonine kinases TOR</term>
</keywords>
<keywords scheme="MESH" qualifier="chemistry" xml:lang="en"><term>Phosphatidylinositol 3-Kinases</term>
</keywords>
<keywords scheme="MESH" qualifier="composition chimique" xml:lang="fr"><term>Antienzymes</term>
<term>Esters</term>
<term>Phosphatidylinositol 3-kinases</term>
<term>Quinoléines</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Phosphatidylinositol 3-Kinases</term>
</keywords>
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<term>Phosphatidylinositol 3-kinases</term>
<term>Quinoléines</term>
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<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antienzymes</term>
<term>Quinoléines</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Molecular Docking Simulation</term>
<term>Phosphoinositide-3 Kinase Inhibitors</term>
<term>Protein Conformation</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Conformation des protéines</term>
<term>Simulation de docking moléculaire</term>
</keywords>
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<front><div type="abstract" xml:lang="en">Using a novel chemistry-based assay for identifying electrophilic natural products in unprocessed extracts, we identified the PI3-kinase/mTOR dual inhibitor neolymphostin A from Salinispora arenicola CNY-486. The method further showed that the vinylogous ester substituent on the neolymphostin core was the exact site for enzyme conjugation. Tandem MS/MS experiments on PI3Kα treated with the inhibitor revealed that neolymphostin covalently modified Lys802 with a shift in mass of +306 amu, corresponding to addition of the inhibitor and elimination of methanol. The binding pose of the inhibitor bound to PI3Kα was modeled, and hydrogen-deuterium exchange mass spectrometry experiments supported this model. Against a panel of kinases, neolymphostin showed good selectivity for PI3-kinase and mTOR. In addition, the natural product blocked AKT phosphorylation in live cells with an IC<sub>50</sub>
 of ∼3 nM. Taken together, neolymphostin is the first reported example of a covalent kinase inhibitor from the bacterial domain of life.</div>
</front>
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<DateCompleted><Year>2019</Year>
<Month>09</Month>
<Day>30</Day>
</DateCompleted>
<DateRevised><Year>2020</Year>
<Month>03</Month>
<Day>09</Day>
</DateRevised>
<Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1520-4804</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>61</Volume>
<Issue>23</Issue>
<PubDate><Year>2018</Year>
<Month>12</Month>
<Day>13</Day>
</PubDate>
</JournalIssue>
<Title>Journal of medicinal chemistry</Title>
<ISOAbbreviation>J Med Chem</ISOAbbreviation>
</Journal>
<ArticleTitle>Neolymphostin A Is a Covalent Phosphoinositide 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Dual Inhibitor That Employs an Unusual Electrophilic Vinylogous Ester.</ArticleTitle>
<Pagination><MedlinePgn>10463-10472</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.1021/acs.jmedchem.8b00975</ELocationID>
<Abstract><AbstractText>Using a novel chemistry-based assay for identifying electrophilic natural products in unprocessed extracts, we identified the PI3-kinase/mTOR dual inhibitor neolymphostin A from Salinispora arenicola CNY-486. The method further showed that the vinylogous ester substituent on the neolymphostin core was the exact site for enzyme conjugation. Tandem MS/MS experiments on PI3Kα treated with the inhibitor revealed that neolymphostin covalently modified Lys802 with a shift in mass of +306 amu, corresponding to addition of the inhibitor and elimination of methanol. The binding pose of the inhibitor bound to PI3Kα was modeled, and hydrogen-deuterium exchange mass spectrometry experiments supported this model. Against a panel of kinases, neolymphostin showed good selectivity for PI3-kinase and mTOR. In addition, the natural product blocked AKT phosphorylation in live cells with an IC<sub>50</sub>
 of ∼3 nM. Taken together, neolymphostin is the first reported example of a covalent kinase inhibitor from the bacterial domain of life.</AbstractText>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Castro-Falcón</LastName>
<ForeName>Gabriel</ForeName>
<Initials>G</Initials>
<AffiliationInfo><Affiliation>Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography , University of California, San Diego , La Jolla , California 92093 , United States.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Seiler</LastName>
<ForeName>Grant S</ForeName>
<Initials>GS</Initials>
<AffiliationInfo><Affiliation>Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography , University of California, San Diego , La Jolla , California 92093 , United States.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 , United States.</Affiliation>
</AffiliationInfo>
</Author>
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<ForeName>Özlem</ForeName>
<Initials>Ö</Initials>
<Identifier Source="ORCID">0000-0002-3317-4731</Identifier>
<AffiliationInfo><Affiliation>Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 , United States.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Rathinaswamy</LastName>
<ForeName>Manoj K</ForeName>
<Initials>MK</Initials>
<AffiliationInfo><Affiliation>Department of Biochemistry and Microbiology , University of Victoria , Victoria , British Columbia V8W 2Y2 , Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Hamelin</LastName>
<ForeName>David</ForeName>
<Initials>D</Initials>
<AffiliationInfo><Affiliation>Department of Biochemistry and Microbiology , University of Victoria , Victoria , British Columbia V8W 2Y2 , Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Hoffmann</LastName>
<ForeName>Reece M</ForeName>
<Initials>RM</Initials>
<AffiliationInfo><Affiliation>Department of Biochemistry and Microbiology , University of Victoria , Victoria , British Columbia V8W 2Y2 , Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Makowski</LastName>
<ForeName>Stefanie L</ForeName>
<Initials>SL</Initials>
<AffiliationInfo><Affiliation>School of Medicine , University of California, San Diego , La Jolla , California , 92093 , United States.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Letzel</LastName>
<ForeName>Anne-Catrin</ForeName>
<Initials>AC</Initials>
<AffiliationInfo><Affiliation>Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography , University of California, San Diego , La Jolla , California 92093 , United States.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Field</LastName>
<ForeName>Seth J</ForeName>
<Initials>SJ</Initials>
<AffiliationInfo><Affiliation>School of Medicine , University of California, San Diego , La Jolla , California , 92093 , United States.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Burke</LastName>
<ForeName>John E</ForeName>
<Initials>JE</Initials>
<AffiliationInfo><Affiliation>Department of Biochemistry and Microbiology , University of Victoria , Victoria , British Columbia V8W 2Y2 , Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Amaro</LastName>
<ForeName>Rommie E</ForeName>
<Initials>RE</Initials>
<Identifier Source="ORCID">0000-0002-9275-9553</Identifier>
<AffiliationInfo><Affiliation>Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 , United States.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Hughes</LastName>
<ForeName>Chambers C</ForeName>
<Initials>CC</Initials>
<Identifier Source="ORCID">0000-0002-7000-6438</Identifier>
<AffiliationInfo><Affiliation>Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography , University of California, San Diego , La Jolla , California 92093 , United States.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
<GrantList CompleteYN="Y"><Grant><GrantID>DP2 OD007237</GrantID>
<Acronym>OD</Acronym>
<Agency>NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>P41 GM103426</GrantID>
<Acronym>GM</Acronym>
<Agency>NIGMS NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>R01 CA201303</GrantID>
<Acronym>CA</Acronym>
<Agency>NCI NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>R01 GM120055</GrantID>
<Acronym>GM</Acronym>
<Agency>NIGMS NIH HHS</Agency>
<Country>United States</Country>
</Grant>
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<PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType>
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<ArticleDate DateType="Electronic"><Year>2018</Year>
<Month>11</Month>
<Day>28</Day>
</ArticleDate>
</Article>
<MedlineJournalInfo><Country>United States</Country>
<MedlineTA>J Med Chem</MedlineTA>
<NlmUniqueID>9716531</NlmUniqueID>
<ISSNLinking>0022-2623</ISSNLinking>
</MedlineJournalInfo>
<ChemicalList><Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D004791">Enzyme Inhibitors</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D004952">Esters</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
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<Chemical><RegistryNumber>0</RegistryNumber>
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<Chemical><RegistryNumber>EC 2.7.1.1</RegistryNumber>
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<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
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</MeshHeading>
<MeshHeading><DescriptorName UI="D019869" MajorTopicYN="N">Phosphatidylinositol 3-Kinases</DescriptorName>
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</MeshHeading>
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<ReferenceList><Reference><Citation>Nat Biotechnol. 2005 Mar;23(3):329-36</Citation>
<ArticleIdList><ArticleId IdType="pubmed">15711537</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4234-9</Citation>
<ArticleIdList><ArticleId IdType="pubmed">16537514</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>ChemMedChem. 2007 Jan;2(1):58-61</Citation>
<ArticleIdList><ArticleId IdType="pubmed">17154430</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>J Med Chem. 2014 Dec 11;57(23):10072-9</Citation>
<ArticleIdList><ArticleId IdType="pubmed">25375838</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Cell. 2017 Aug 10;170(4):605-635</Citation>
<ArticleIdList><ArticleId IdType="pubmed">28802037</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Angew Chem Int Ed Engl. 2017 Nov 27;56(48):15200-15209</Citation>
<ArticleIdList><ArticleId IdType="pubmed">28853194</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>J Am Chem Soc. 2005 Jan 12;127(1):217-24</Citation>
<ArticleIdList><ArticleId IdType="pubmed">15631471</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>J Natl Cancer Inst. 1989 Jul 19;81(14):1088-92</Citation>
<ArticleIdList><ArticleId IdType="pubmed">2738938</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>J Antibiot (Tokyo). 1977 Apr;30(4):275-82</Citation>
<ArticleIdList><ArticleId IdType="pubmed">863788</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Nat Chem Biol. 2018 Aug;14(8):768-777</Citation>
<ArticleIdList><ArticleId IdType="pubmed">29942081</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>J Am Chem Soc. 2011 Aug 31;133(34):13311-3</Citation>
<ArticleIdList><ArticleId IdType="pubmed">21815669</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Nature. 1995 Jul 27;376(6538):313-20</Citation>
<ArticleIdList><ArticleId IdType="pubmed">7630397</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>J Am Chem Soc. 2018 Jan 24;140(3):932-939</Citation>
<ArticleIdList><ArticleId IdType="pubmed">29232121</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Mol Cell Biol. 1996 Apr;16(4):1722-33</Citation>
<ArticleIdList><ArticleId IdType="pubmed">8657148</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>J Am Chem Soc. 2016 Aug 24;138(33):10554-60</Citation>
<ArticleIdList><ArticleId IdType="pubmed">27478969</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>ACS Chem Biol. 2014 Sep 19;9(9):2014-22</Citation>
<ArticleIdList><ArticleId IdType="pubmed">24937678</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Biochem Pharmacol. 2006 Nov 15;72(10):1311-21</Citation>
<ArticleIdList><ArticleId IdType="pubmed">16984800</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Methods Enzymol. 2017;583:143-172</Citation>
<ArticleIdList><ArticleId IdType="pubmed">28063489</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>ACS Chem Biol. 2014 May 16;9(5):1086-91</Citation>
<ArticleIdList><ArticleId IdType="pubmed">24556163</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>EMBO J. 1996 Oct 1;15(19):5256-67</Citation>
<ArticleIdList><ArticleId IdType="pubmed">8895571</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Cancer Cell. 2002 Jun;1(5):433-43</Citation>
<ArticleIdList><ArticleId IdType="pubmed">12124173</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):442-6</Citation>
<ArticleIdList><ArticleId IdType="pubmed">8421674</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):12022-7</Citation>
<ArticleIdList><ArticleId IdType="pubmed">9751783</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Chem Biol. 2001 Aug;8(8):759-66</Citation>
<ArticleIdList><ArticleId IdType="pubmed">11514225</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Nat Prod Rep. 2012 Mar;29(3):392-403</Citation>
<ArticleIdList><ArticleId IdType="pubmed">22231144</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Nat Biotechnol. 2008 Jan;26(1):127-32</Citation>
<ArticleIdList><ArticleId IdType="pubmed">18183025</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Chem Biol. 2013 Feb 21;20(2):146-59</Citation>
<ArticleIdList><ArticleId IdType="pubmed">23438744</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Nat Rev Cancer. 2009 Jan;9(1):28-39</Citation>
<ArticleIdList><ArticleId IdType="pubmed">19104514</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>J Med Chem. 2015 Mar 12;58(5):2091-113</Citation>
<ArticleIdList><ArticleId IdType="pubmed">25634295</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>J Antibiot (Tokyo). 1975 Oct;28(10):721-6</Citation>
<ArticleIdList><ArticleId IdType="pubmed">1102508</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Nat Rev Cancer. 2006 Oct;6(10):813-23</Citation>
<ArticleIdList><ArticleId IdType="pubmed">16990858</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>ACS Chem Biol. 2018 Jan 19;13(1):36-44</Citation>
<ArticleIdList><ArticleId IdType="pubmed">29202222</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Nat Prod Rep. 2012 Jun;29(6):659-82</Citation>
<ArticleIdList><ArticleId IdType="pubmed">22504336</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Biochem J. 1993 Dec 1;296 ( Pt 2):297-301</Citation>
<ArticleIdList><ArticleId IdType="pubmed">8257416</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Science. 2005 May 27;308(5726):1318-21</Citation>
<ArticleIdList><ArticleId IdType="pubmed">15919995</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>J Antibiot (Tokyo). 1997 Jul;50(7):537-42</Citation>
<ArticleIdList><ArticleId IdType="pubmed">9711243</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Chemistry. 2015 Feb 23;21(9):3701-7</Citation>
<ArticleIdList><ArticleId IdType="pubmed">25605563</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Org Lett. 2017 May 5;19(9):2270-2273</Citation>
<ArticleIdList><ArticleId IdType="pubmed">28425713</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>N Engl J Med. 2014 Mar 13;370(11):997-1007</Citation>
<ArticleIdList><ArticleId IdType="pubmed">24450857</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>J Antibiot (Tokyo). 1997 Jul;50(7):543-5</Citation>
<ArticleIdList><ArticleId IdType="pubmed">9711244</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Environ Sci Technol. 2012 Aug 21;46(16):8937-44</Citation>
<ArticleIdList><ArticleId IdType="pubmed">22834560</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>ACS Chem Biol. 2016 Aug 19;11(8):2328-36</Citation>
<ArticleIdList><ArticleId IdType="pubmed">27294329</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Biosci Biotechnol Biochem. 2002 Mar;66(3):501-7</Citation>
<ArticleIdList><ArticleId IdType="pubmed">12005041</ArticleId>
</ArticleIdList>
</Reference>
<Reference><Citation>Biochem J. 2017 May 16;474(11):1867-1877</Citation>
<ArticleIdList><ArticleId IdType="pubmed">28381646</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
</PubmedData>
</pubmed>
<affiliations><list><country><li>Canada</li>
<li>États-Unis</li>
</country>
</list>
<tree><country name="États-Unis"><noRegion><name sortKey="Castro Falc N, Gabriel" sort="Castro Falc N, Gabriel" uniqKey="Castro Falc N G" first="Gabriel" last="Castro-Falc N">Gabriel Castro-Falc N</name>
</noRegion>
<name sortKey="Amaro, Rommie E" sort="Amaro, Rommie E" uniqKey="Amaro R" first="Rommie E" last="Amaro">Rommie E. Amaro</name>
<name sortKey="Demir, Ozlem" sort="Demir, Ozlem" uniqKey="Demir O" first="Özlem" last="Demir">Özlem Demir</name>
<name sortKey="Field, Seth J" sort="Field, Seth J" uniqKey="Field S" first="Seth J" last="Field">Seth J. Field</name>
<name sortKey="Hughes, Chambers C" sort="Hughes, Chambers C" uniqKey="Hughes C" first="Chambers C" last="Hughes">Chambers C. Hughes</name>
<name sortKey="Letzel, Anne Catrin" sort="Letzel, Anne Catrin" uniqKey="Letzel A" first="Anne-Catrin" last="Letzel">Anne-Catrin Letzel</name>
<name sortKey="Makowski, Stefanie L" sort="Makowski, Stefanie L" uniqKey="Makowski S" first="Stefanie L" last="Makowski">Stefanie L. Makowski</name>
<name sortKey="Seiler, Grant S" sort="Seiler, Grant S" uniqKey="Seiler G" first="Grant S" last="Seiler">Grant S. Seiler</name>
<name sortKey="Seiler, Grant S" sort="Seiler, Grant S" uniqKey="Seiler G" first="Grant S" last="Seiler">Grant S. Seiler</name>
</country>
<country name="Canada"><noRegion><name sortKey="Rathinaswamy, Manoj K" sort="Rathinaswamy, Manoj K" uniqKey="Rathinaswamy M" first="Manoj K" last="Rathinaswamy">Manoj K. Rathinaswamy</name>
</noRegion>
<name sortKey="Burke, John E" sort="Burke, John E" uniqKey="Burke J" first="John E" last="Burke">John E. Burke</name>
<name sortKey="Hamelin, David" sort="Hamelin, David" uniqKey="Hamelin D" first="David" last="Hamelin">David Hamelin</name>
<name sortKey="Hoffmann, Reece M" sort="Hoffmann, Reece M" uniqKey="Hoffmann R" first="Reece M" last="Hoffmann">Reece M. Hoffmann</name>
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   |texte=   Neolymphostin A Is a Covalent Phosphoinositide 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Dual Inhibitor That Employs an Unusual Electrophilic Vinylogous Ester.
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Neolymphostin A Is a Covalent Phosphoinositide 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Dual Inhibitor That Employs an Unusual Electrophilic Vinylogous Ester.

Neolymphostin A Is a Covalent Phosphoinositide 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Dual Inhibitor That Employs an Unusual Electrophilic Vinylogous Ester.

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