癌症研究
BRD4
溴尿嘧啶
生物
髓系白血病
下调和上调
多发性骨髓瘤
白血病
乙酰化
免疫学
基因
遗传学
作者
Luciano Nicosia,Gary J. Spencer,Nigel Brooks,Fabio M. R. Amaral,Naseer J. Basma,John Chadwick,Bradley Revell,Bettina Wingelhofer,Alba Maiques‐Diaz,Oliver Sinclair,Francesco Camera,Filippo Ciceri,Daniel H. Wiseman,Neil Pegg,Will West,Tomasz Knurowski,Kris Frese,Karen Clegg,Victoria Campbell,James Cavet,Mhairi Copland,Emma Searle,Tim C. P. Somervaille
出处
期刊:Cancer Cell
[Elsevier]
日期:2023-12-01
卷期号:41 (12): 2136-2153.e13
被引量:8
标识
DOI:10.1016/j.ccell.2023.11.001
摘要
CCS1477 (inobrodib) is a potent, selective EP300/CBP bromodomain inhibitor which induces cell-cycle arrest and differentiation in hematologic malignancy model systems. In myeloid leukemia cells, it promotes rapid eviction of EP300/CBP from an enhancer subset marked by strong MYB occupancy and high H3K27 acetylation, with downregulation of the subordinate oncogenic network and redistribution to sites close to differentiation genes. In myeloma cells, CCS1477 induces eviction of EP300/CBP from FGFR3, the target of the common (4; 14) translocation, with redistribution away from IRF4-occupied sites to TCF3/E2A-occupied sites. In a subset of patients with relapsed or refractory disease, CCS1477 monotherapy induces differentiation responses in AML and objective responses in heavily pre-treated multiple myeloma. In vivo preclinical combination studies reveal synergistic responses to treatment with standard-of-care agents. Thus, CCS1477 exhibits encouraging preclinical and early-phase clinical activity by disrupting recruitment of EP300/CBP to enhancer networks occupied by critical transcription factors.
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