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https://ahro.austin.org.au/austinjspui/handle/1/33669| Title: | Rationally designed chimeric PI3K-BET bromodomain inhibitors elicit curative responses in MYC-driven lymphoma. | Austin Authors: | Oh, Danielle H;Ma, Xiao;Hogg, Simon J;He, Jackson;Kearney, Conor;Brasacchio, Daniella;Susanto, Olivia;Maher, Belinda;Jennings, Ian G;Newbold, Andrea;Fraser, Peter;Gruber, Emily;Kats, Lev M;Gregory, Gareth P;Johnstone, Ricky W;Thompson, Philip E;Shortt, Jake | Affiliation: | Blood 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. Medicinal 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. Cancer Biology Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne VIC 3000, Australia.;Oncology Discovery Research, Abbvie, South San Francisco, CA 94080. Blood 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. Olivia Newton-John Cancer Research Institute Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville VIC 3052, 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. 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. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville VIC 3052, Australia. Blood 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. |
Issue Date: | 5-Sep-2023 | Date: | 2023 | Publication information: | Proceedings of the National Academy of Sciences of the United States of America 2023-09-05; 120(36) | Abstract: | Targeted 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. | URI: | https://ahro.austin.org.au/austinjspui/handle/1/33669 | DOI: | 10.1073/pnas.2306414120 | ORCID: | 0000-0001-9804-1449 0000-0002-9842-9045 0000-0002-3154-5121 0000-0001-5956-9611 0000-0002-8900-6876 0009-0001-6955-4955 0000-0001-8742-8138 0000-0002-5910-7625 0000-0003-3185-6488 |
Journal: | Proceedings of the National Academy of Sciences of the United States of America | Start page: | e2306414120 | PubMed URL: | 37643213 | ISSN: | 1091-6490 | Type: | Journal Article | Subjects: | BET-bromodomains cMYC chimeric small molecules phosphatidylinositol-3-kinase Lymphoma/drug therapy |
| Appears in Collections: | Journal articles |
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