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<PubmedArticleSet><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">14704432</PMID><DateCompleted><Year>2004</Year><Month>03</Month><Day>04</Day></DateCompleted><DateRevised><Year>2016</Year><Month>11</Month><Day>24</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1095-9203</ISSN><JournalIssue CitedMedium="Internet"><Volume>303</Volume><Issue>5659</Issue><PubDate><Year>2004</Year><Month>Feb</Month><Day>06</Day></PubDate></JournalIssue><Title>Science (New York, N.Y.)</Title><ISOAbbreviation>Science</ISOAbbreviation></Journal><ArticleTitle>In vivo activation of the p53 pathway by small-molecule antagonists of MDM2.</ArticleTitle><Pagination><MedlinePgn>844-8</MedlinePgn></Pagination><Abstract><AbstractText>MDM2 binds the p53 tumor suppressor protein with high affinity and negatively modulates its transcriptional activity and stability. Overexpression of MDM2, found in many human tumors, effectively impairs p53 function. Inhibition of MDM2-p53 interaction can stabilize p53 and may offer a novel strategy for cancer therapy. Here, we identify potent and selective small-molecule antagonists of MDM2 and confirm their mode of action through the crystal structures of complexes. These compounds bind MDM2 in the p53-binding pocket and activate the p53 pathway in cancer cells, leading to cell cycle arrest, apoptosis, and growth inhibition of human tumor xenografts in nude mice.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Vassilev</LastName><ForeName>Lyubomir T</ForeName><Initials>LT</Initials><AffiliationInfo><Affiliation>Department of Discovery Oncology, Roche Research Center, Hoffmann-La Roche, Inc., Nutley, NJ 07110, USA. lyubomir.vassilev@roche.com</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Vu</LastName><ForeName>Binh T</ForeName><Initials>BT</Initials></Author><Author ValidYN="Y"><LastName>Graves</LastName><ForeName>Bradford</ForeName><Initials>B</Initials></Author><Author ValidYN="Y"><LastName>Carvajal</LastName><ForeName>Daisy</ForeName><Initials>D</Initials></Author><Author ValidYN="Y"><LastName>Podlaski</LastName><ForeName>Frank</ForeName><Initials>F</Initials></Author><Author ValidYN="Y"><LastName>Filipovic</LastName><ForeName>Zoran</ForeName><Initials>Z</Initials></Author><Author ValidYN="Y"><LastName>Kong</LastName><ForeName>Norman</ForeName><Initials>N</Initials></Author><Author ValidYN="Y"><LastName>Kammlott</LastName><ForeName>Ursula</ForeName><Initials>U</Initials></Author><Author ValidYN="Y"><LastName>Lukacs</LastName><ForeName>Christine</ForeName><Initials>C</Initials></Author><Author ValidYN="Y"><LastName>Klein</LastName><ForeName>Christian</ForeName><Initials>C</Initials></Author><Author ValidYN="Y"><LastName>Fotouhi</LastName><ForeName>Nader</ForeName><Initials>N</Initials></Author><Author ValidYN="Y"><LastName>Liu</LastName><ForeName>Emily A</ForeName><Initials>EA</Initials></Author></AuthorList><Language>eng</Language><DataBankList CompleteYN="Y"><DataBank><DataBankName>PDB</DataBankName><AccessionNumberList><AccessionNumber>1RV1</AccessionNumber></AccessionNumberList></DataBank></DataBankList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2004</Year><Month>01</Month><Day>02</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Science</MedlineTA><NlmUniqueID>0404511</NlmUniqueID><ISSNLinking>0036-8075</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C493956">CDKN1A protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C493957">Cdkn1a protein, mouse</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D050759">Cyclin-Dependent Kinase Inhibitor p21</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D016213">Cyclins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D007093">Imidazoles</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D009687">Nuclear Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D010879">Piperazines</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011518">Proto-Oncogene Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D016159">Tumor Suppressor Protein p53</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C482203">nutlin 1</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C482204">nutlin 2</NameOfSubstance></Chemical><Chemical><RegistryNumber>53IA0V845C</RegistryNumber><NameOfSubstance UI="C482205">nutlin 3</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.3.2.27</RegistryNumber><NameOfSubstance UI="C497206">MDM2 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.3.2.27</RegistryNumber><NameOfSubstance UI="C497207">Mdm2 protein, mouse</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.3.2.27</RegistryNumber><NameOfSubstance UI="D051736">Proto-Oncogene Proteins c-mdm2</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017209" MajorTopicYN="N">Apoptosis</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001665" MajorTopicYN="N">Binding Sites</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002453" MajorTopicYN="N">Cell Cycle</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002455" MajorTopicYN="N">Cell Division</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002460" MajorTopicYN="N">Cell Line</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D045744" MajorTopicYN="N">Cell Line, Tumor</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002470" MajorTopicYN="N">Cell Survival</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D003460" MajorTopicYN="N">Crystallization</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018360" MajorTopicYN="N">Crystallography, X-Ray</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D050759" MajorTopicYN="N">Cyclin-Dependent Kinase Inhibitor p21</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D016213" MajorTopicYN="N">Cyclins</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004305" MajorTopicYN="N">Dose-Response Relationship, Drug</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015870" MajorTopicYN="N">Gene Expression</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D016158" MajorTopicYN="N">Genes, p53</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D057927" MajorTopicYN="N">Hydrophobic and Hydrophilic Interactions</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007093" MajorTopicYN="N">Imidazoles</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008819" MajorTopicYN="N">Mice, Nude</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008958" MajorTopicYN="N">Models, Molecular</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008970" MajorTopicYN="N">Molecular Weight</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D041681" MajorTopicYN="N">NIH 3T3 Cells</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009368" MajorTopicYN="N">Neoplasm Transplantation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009374" MajorTopicYN="N">Neoplasms, Experimental</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="N">drug therapy</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000473" MajorTopicYN="Y">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D009687" MajorTopicYN="Y">Nuclear Proteins</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D010766" MajorTopicYN="N">Phosphorylation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D010879" MajorTopicYN="N">Piperazines</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011487" MajorTopicYN="N">Protein Conformation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011518" MajorTopicYN="N">Proto-Oncogene Proteins</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="Y">antagonists &amp; inhibitors</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051736" MajorTopicYN="N">Proto-Oncogene Proteins c-mdm2</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D013237" MajorTopicYN="N">Stereoisomerism</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D014183" MajorTopicYN="N">Transplantation, Heterologous</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D016159" MajorTopicYN="N">Tumor Suppressor Protein p53</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2004</Year><Month>1</Month><Day>6</Day><Hour>5</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2004</Year><Month>3</Month><Day>5</Day><Hour>5</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2004</Year><Month>1</Month><Day>6</Day><Hour>5</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">14704432</ArticleId><ArticleId IdType="doi">10.1126/science.1092472</ArticleId><ArticleId IdType="pii">1092472</ArticleId></ArticleIdList></PubmedData></PubmedArticle></PubmedArticleSet>