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Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression
dc.contributor.authorQin, Chong
dc.contributor.authorHu, Yang
dc.contributor.authorZhou, Bing
dc.contributor.authorFernandez-Salas, Ester
dc.contributor.authorYang, Chao-Yie
dc.contributor.authorLiu, Liu
dc.contributor.authorMcEachern, Donna
dc.contributor.authorPrzybranowski, Sally
dc.contributor.authorWang, Mi
dc.contributor.authorStuckey, Jeanne
dc.contributor.authorMeagher, Jennifer
dc.contributor.authorBai, Longchuan
dc.contributor.authorChen, Zhuo
dc.contributor.authorLin, Mei
dc.contributor.authorYang, Jiuling
dc.contributor.authorZiazadeh, Danya N
dc.contributor.authorXu, Fuming
dc.contributor.authorHu, Jiantao
dc.contributor.authorXiang, Weiguo
dc.contributor.authorHuang, Liyue
dc.contributor.authorLi, Siwei
dc.contributor.authorWen, Bo
dc.contributor.authorSun, Duxin
dc.contributor.authorWang, Shaomeng
dc.coverage.spatialUnited States
dc.date.accessioned2024-01-23T21:20:06Z
dc.date.available2024-01-23T21:20:06Z
dc.date.issued2018-07-18
dc.identifier.issn0022-2623
dc.identifier.issn1520-4804
dc.identifier.urihttps://www.ncbi.nlm.nih.gov/pubmed/30019901
dc.identifier.urihttps://hdl.handle.net/2027.42/192135en
dc.description.abstractProteins of the bromodomain and extra-terminal (BET) family are epigenetics "readers" and promising therapeutic targets for cancer and other human diseases. We describe herein a structure-guided design of [1,4]oxazepines as a new class of BET inhibitors and our subsequent design, synthesis, and evaluation of proteolysis-targeting chimeric (PROTAC) small-molecule BET degraders. Our efforts have led to the discovery of extremely potent BET degraders, exemplified by QCA570, which effectively induces degradation of BET proteins and inhibits cell growth in human acute leukemia cell lines even at low picomolar concentrations. QCA570 achieves complete and durable tumor regression in leukemia xenograft models in mice at well-tolerated dose-schedules. QCA570 is the most potent and efficacious BET degrader reported to date.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherAmerican Chemical Society (ACS)
dc.subjectAnimals
dc.subjectCell Line, Tumor
dc.subjectDose-Response Relationship, Drug
dc.subjectDrug Design
dc.subjectFemale
dc.subjectHumans
dc.subjectMice
dc.subjectModels, Molecular
dc.subjectProtein Conformation
dc.subjectProteins
dc.subjectProteolysis
dc.subjectSmall Molecule Libraries
dc.titleDiscovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression
dc.typeArticle
dc.identifier.pmid30019901
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/192135/2/qin-et-al-2018-discovery-of-qca570-as-an-exceptionally-potent-and-efficacious-proteolysis-targeting-chimera-(protac).pdf
dc.identifier.doi10.1021/acs.jmedchem.8b00506
dc.identifier.doihttps://dx.doi.org/10.7302/22135
dc.identifier.sourceJournal of medicinal chemistry
dc.description.versionPublished version
dc.date.updated2024-01-23T21:20:03Z
dc.identifier.orcid0000-0002-5445-0109
dc.identifier.orcid0000-0002-5908-4072
dc.identifier.orcid0000-0002-4192-8900
dc.identifier.orcid0000-0003-1025-2925
dc.identifier.orcid0000-0002-6406-2126
dc.identifier.orcid0000-0002-8782-6950
dc.identifier.volume61
dc.identifier.issue15
dc.identifier.startpage6685
dc.identifier.endpage6704
dc.identifier.name-orcidQin, Chong
dc.identifier.name-orcidHu, Yang
dc.identifier.name-orcidZhou, Bing
dc.identifier.name-orcidFernandez-Salas, Ester
dc.identifier.name-orcidYang, Chao-Yie; 0000-0002-5445-0109
dc.identifier.name-orcidLiu, Liu
dc.identifier.name-orcidMcEachern, Donna
dc.identifier.name-orcidPrzybranowski, Sally
dc.identifier.name-orcidWang, Mi; 0000-0002-5908-4072
dc.identifier.name-orcidStuckey, Jeanne; 0000-0002-4192-8900
dc.identifier.name-orcidMeagher, Jennifer
dc.identifier.name-orcidBai, Longchuan; 0000-0003-1025-2925
dc.identifier.name-orcidChen, Zhuo
dc.identifier.name-orcidLin, Mei
dc.identifier.name-orcidYang, Jiuling
dc.identifier.name-orcidZiazadeh, Danya N
dc.identifier.name-orcidXu, Fuming
dc.identifier.name-orcidHu, Jiantao
dc.identifier.name-orcidXiang, Weiguo
dc.identifier.name-orcidHuang, Liyue
dc.identifier.name-orcidLi, Siwei
dc.identifier.name-orcidWen, Bo
dc.identifier.name-orcidSun, Duxin; 0000-0002-6406-2126
dc.identifier.name-orcidWang, Shaomeng; 0000-0002-8782-6950
dc.working.doi10.7302/22135en
dc.owningcollnameInternal Medicine, Department of


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