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Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/33669
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dc.contributor.authorOh, Danielle H-
dc.contributor.authorMa, Xiao-
dc.contributor.authorHogg, Simon J-
dc.contributor.authorHe, Jackson-
dc.contributor.authorKearney, Conor-
dc.contributor.authorBrasacchio, Daniella-
dc.contributor.authorSusanto, Olivia-
dc.contributor.authorMaher, Belinda-
dc.contributor.authorJennings, Ian G-
dc.contributor.authorNewbold, Andrea-
dc.contributor.authorFraser, Peter-
dc.contributor.authorGruber, Emily-
dc.contributor.authorKats, Lev M-
dc.contributor.authorGregory, Gareth P-
dc.contributor.authorJohnstone, Ricky W-
dc.contributor.authorThompson, Philip E-
dc.contributor.authorShortt, Jake-
dc.date2023-
dc.date.accessioned2023-09-06T07:03:32Z-
dc.date.available2023-09-06T07:03:32Z-
dc.date.issued2023-09-05-
dc.identifier.citationProceedings of the National Academy of Sciences of the United States of America 2023-09-05; 120(36)en_US
dc.identifier.issn1091-6490-
dc.identifier.urihttps://ahro.austin.org.au/austinjspui/handle/1/33669-
dc.description.abstractTargeted inhibitors of bromodomain and extraterminal (BET)-bromodomains and phosphatidylinositol-3-kinase (PI3K) signaling demonstrate potent but self-limited antilymphoma activity as single agents in the context of cellular Myelocytomatosis (cMYC) oncogene-dysregulation. However, combined PI3K and BET inhibition imparts synergistic anticancer activity with the potential for more sustained disease responses due to the mutual antagonism of compensatory epigenetic and signaling networks. Here, we describe the mechanistic and therapeutic validation of rationally designed dual PI3K/BET bromodomain inhibitors, built by linkage of established PI3K and BET inhibitor pharmacophores. The lead candidate demonstrates high selectivity, nanomolar range cellular potency, and compelling in vivo efficacy, including curative responses in the aggressive Eµ-Myc lymphoma model. These studies further support the therapeutic strategy of combined PI3K and BET inhibition and provide a potential step-change in approach to orthogonal MYC antagonism using optimized chimeric small-molecule technology.en_US
dc.language.isoeng-
dc.subjectBET-bromodomainsen_US
dc.subjectcMYCen_US
dc.subjectchimeric small moleculesen_US
dc.subjectphosphatidylinositol-3-kinaseen_US
dc.titleRationally designed chimeric PI3K-BET bromodomain inhibitors elicit curative responses in MYC-driven lymphoma.en_US
dc.typeJournal Articleen_US
dc.identifier.journaltitleProceedings of the National Academy of Sciences of the United States of Americaen_US
dc.identifier.affiliationBlood Cancer Therapeutics Laboratory, School of Clinical Sciences at Monash Health, Faculty of Medicine Nursing and Health Sciences, Monash University, Melbourne VIC 3168, Australia.;Monash Haematology, Monash Health, Melbourne VIC 3168, Australia.;Cancer Biology Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne VIC 3000, Australia.en_US
dc.identifier.affiliationMedicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville VIC 3052, Australia.;Department of Systems Biology, Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115.en_US
dc.identifier.affiliationCancer Biology Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne VIC 3000, Australia.;Oncology Discovery Research, Abbvie, South San Francisco, CA 94080.en_US
dc.identifier.affiliationBlood Cancer Therapeutics Laboratory, School of Clinical Sciences at Monash Health, Faculty of Medicine Nursing and Health Sciences, Monash University, Melbourne VIC 3168, Australia.;Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville VIC 3052, Australia.en_US
dc.identifier.affiliationOlivia Newton-John Cancer Research Instituteen_US
dc.identifier.affiliationMedicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville VIC 3052, Australia.en_US
dc.identifier.affiliationCancer Biology Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne VIC 3000, Australia.;Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Melbourne VIC 3000, Australia.en_US
dc.identifier.affiliationCancer Biology Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne VIC 3000, Australia.;Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Melbourne VIC 3000, Australia.en_US
dc.identifier.affiliationMedicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville VIC 3052, Australia.en_US
dc.identifier.affiliationBlood Cancer Therapeutics Laboratory, School of Clinical Sciences at Monash Health, Faculty of Medicine Nursing and Health Sciences, Monash University, Melbourne VIC 3168, Australia.;Monash Haematology, Monash Health, Melbourne VIC 3168, Australia.;Cancer Biology Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne VIC 3000, Australia.;Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Melbourne VIC 3000, Australia.en_US
dc.identifier.doi10.1073/pnas.2306414120en_US
dc.type.contentTexten_US
dc.identifier.orcid0000-0001-9804-1449en_US
dc.identifier.orcid0000-0002-9842-9045en_US
dc.identifier.orcid0000-0002-3154-5121en_US
dc.identifier.orcid0000-0001-5956-9611en_US
dc.identifier.orcid0000-0002-8900-6876en_US
dc.identifier.orcid0009-0001-6955-4955en_US
dc.identifier.orcid0000-0001-8742-8138en_US
dc.identifier.orcid0000-0002-5910-7625en_US
dc.identifier.orcid0000-0003-3185-6488en_US
dc.identifier.pubmedid37643213-
dc.description.volume120-
dc.description.issue36-
dc.description.startpagee2306414120-
dc.subject.meshtermssecondaryLymphoma/drug therapy-
item.grantfulltextnone-
item.openairetypeJournal Article-
item.languageiso639-1en-
item.fulltextNo Fulltext-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.cerifentitytypePublications-
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