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

Noha A. M. Shendy, Melissa Bikowitz, Logan H. Sigua, Yang Zhang, Audrey Mercier, Yousef Khashana, Stephanie Nance, Qi Liu, Ian M. Delahunty, Sarah Robinson, Vanshita Goel, Matthew G. Rees, Melissa A. Ronan, Tingjian Wang, Mustafa Kocak, Jennifer A. Roth, Yingzhe Wang, Burgess B. Freeman, Brent A. Orr, Brian J. Abraham, Martine F. Roussel, Ernst Schonbrunn (), Jun Qi () and Adam D. Durbin ()
Additional contact information
Noha A. M. Shendy: St. Jude Children’s Research Hospital
Melissa Bikowitz: Moffitt Cancer Center
Logan H. Sigua: Dana-Farber Cancer Institute
Yang Zhang: St. Jude Children’s Research Hospital
Audrey Mercier: St. Jude Children’s Research Hospital
Yousef Khashana: St. Jude Children’s Research Hospital
Stephanie Nance: St. Jude Children’s Research Hospital
Qi Liu: Dana-Farber Cancer Institute
Ian M. Delahunty: St. Jude Children’s Research Hospital
Sarah Robinson: St. Jude Children’s Research Hospital
Vanshita Goel: St. Jude Children’s Research Hospital
Matthew G. Rees: The Broad Institute of MIT and Harvard
Melissa A. Ronan: The Broad Institute of MIT and Harvard
Tingjian Wang: Dana-Farber Cancer Institute
Mustafa Kocak: The Broad Institute of MIT and Harvard
Jennifer A. Roth: The Broad Institute of MIT and Harvard
Yingzhe Wang: St Jude Children’s Research Hospital
Burgess B. Freeman: St Jude Children’s Research Hospital
Brent A. Orr: St Jude Children’s Research Hospital
Brian J. Abraham: St. Jude Children’s Research Hospital
Martine F. Roussel: St. Jude Children’s Research Hospital
Ernst Schonbrunn: Moffitt Cancer Center
Jun Qi: Dana-Farber Cancer Institute
Adam D. Durbin: St. Jude Children’s Research Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-47102-0

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