Group 3 medulloblastoma transcriptional networks collapse under domain specific EP300/CBP inhibition.

Autor: Shendy NAM; Division of Molecular Oncology, Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA., Bikowitz M; Drug Discovery Department, Moffitt Cancer Center, Tampa, FL, USA.; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA., Sigua LH; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA., Zhang Y; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Mercier A; Tumor Cell Biology Department, St. Jude Children's Research Hospital, Memphis, TN, USA., Khashana Y; Division of Molecular Oncology, Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA., Nance S; Division of Molecular Oncology, Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA., Liu Q; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA., Delahunty IM; Division of Molecular Oncology, Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA., Robinson S; Tumor Cell Biology Department, St. Jude Children's Research Hospital, Memphis, TN, USA., Goel V; Tumor Cell Biology Department, St. Jude Children's Research Hospital, Memphis, TN, USA., Rees MG; The Broad Institute of MIT and Harvard, Cambridge, MA, USA., Ronan MA; The Broad Institute of MIT and Harvard, Cambridge, MA, USA., Wang T; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA., Kocak M; The Broad Institute of MIT and Harvard, Cambridge, MA, USA., Roth JA; The Broad Institute of MIT and Harvard, Cambridge, MA, USA., Wang Y; Preclinical Pharmacokinetics Shared Resource, St Jude Children's Research Hospital, Memphis, TN, USA., Freeman BB; Preclinical Pharmacokinetics Shared Resource, St Jude Children's Research Hospital, Memphis, TN, USA., Orr BA; Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA., Abraham BJ; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Roussel MF; Tumor Cell Biology Department, St. Jude Children's Research Hospital, Memphis, TN, USA., Schonbrunn E; Drug Discovery Department, Moffitt Cancer Center, Tampa, FL, USA. Ernst.Schonbrunn@moffitt.org.; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA. Ernst.Schonbrunn@moffitt.org., Qi J; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. jun_qi@dfci.harvard.edu.; Department of Medicine, Harvard Medical School, Boston, MA, USA. jun_qi@dfci.harvard.edu., Durbin AD; Division of Molecular Oncology, Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA. adam.durbin@stjude.org.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Apr 25; Vol. 15 (1), pp. 3483. Date of Electronic Publication: 2024 Apr 25.
DOI: 10.1038/s41467-024-47102-0
Abstrakt: Chemical discovery efforts commonly target individual protein domains. Many proteins, including the EP300/CBP histone acetyltransferases (HATs), contain several targetable domains. EP300/CBP are critical gene-regulatory targets in cancer, with existing high potency inhibitors of either the catalytic HAT domain or protein-binding bromodomain (BRD). A domain-specific inhibitory approach to multidomain-containing proteins may identify exceptional-responding tumor types, thereby expanding a therapeutic index. Here, we discover that targeting EP300/CBP using the domain-specific inhibitors, A485 (HAT) or CCS1477 (BRD) have different effects in select tumor types. Group 3 medulloblastoma (G3MB) cells are especially sensitive to BRD, compared with HAT inhibition. Structurally, these effects are mediated by the difluorophenyl group in the catalytic core of CCS1477. Mechanistically, bromodomain inhibition causes rapid disruption of genetic dependency networks that are required for G3MB growth. These studies provide a domain-specific structural foundation for drug discovery efforts targeting EP300/CBP and identify a selective role for the EP300/CBP bromodomain in maintaining genetic dependency networks in G3MB.
(© 2024. The Author(s).)
Databáze: MEDLINE
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