2. Academic Validation
  3. Therapeutic targeting of EP300/CBP by bromodomain inhibition in hematologic malignancies

Therapeutic targeting of EP300/CBP by bromodomain inhibition in hematologic malignancies

  • Cancer Cell. 2023 Nov 17:S1535-6108(23)00366-5. doi: 10.1016/j.ccell.2023.11.001.
Luciano Nicosia 1,  Gary J Spencer 1,  Nigel Brooks 2,  Fabio M R Amaral 1,  Naseer J Basma 1,  John A Chadwick 1,  Bradley Revell 1,  Bettina Wingelhofer 1,  Alba Maiques-Diaz 1,  Oliver Sinclair 1,  Francesco Camera 1,  Filippo Ciceri 1,  Daniel H Wiseman 3,  Neil Pegg 2,  Will West 2,  Tomasz Knurowski 2,  Kris Frese 2,  Karen Clegg 2,  Victoria L Campbell 4,  James Cavet 5,  Mhairi Copland 6,  Emma Searle 5,  Tim C P Somervaille 7
Affiliations

Affiliations

  • 1 Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
  • 2 CellCentric Ltd., Cambridge CB10 1XL, UK.
  • 3 Epigenetics of Haematopoiesis Group, The University of Manchester, Manchester M20 4BX, UK.
  • 4 Western General Hospital, Edinburgh EH4 2XU, UK.
  • 5 The Christie NHS Foundation Trust, Manchester M20 4BX, UK.
  • 6 Paul O'Gorman Leukaemia Research Centre, University of Glasgow, Glasgow G12 0YN, UK.
  • 7 Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK; The Christie NHS Foundation Trust, Manchester M20 4BX, UK. Electronic address: tim.somervaille@cruk.manchester.ac.uk.
PMID: 37995682 DOI: 10.1016/j.ccell.2023.11.001
Abstract

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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