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Therapeutic targeting of EP300/CBP by bromodomain inhibition in hematologic malignancies
Nicosia, Luciano Spencer, Gary J. Brooks, N. Amaral, Fabio M R Basma, Nasar J Chadwick, John A Revell, Bradley Wingelhofer, Bettina Maiques-Diaz, Alba Sinclair, Oliver
Nicosia, Luciano
Spencer, Gary J.
Brooks, N.
Amaral, Fabio M R
Basma, Nasar J
Chadwick, John A
Revell, Bradley
Wingelhofer, Bettina
Maiques-Diaz, Alba
Sinclair, Oliver
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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.
Authors
Nicosia, Luciano
Spencer, Gary J.
Brooks, N.
Amaral, Fabio M R
Basma, Nasar J
Chadwick, John A
Revell, Bradley
Wingelhofer, Bettina
Maiques-Diaz, Alba
Sinclair, Oliver
Camera, Franncesco
Ciceri, Filippo
Wiseman, D. H.
Pegg, N.
West, W.
Knurowski, T.
Frese, K.
Clegg, K.
Campbell, V. L.
Cavet, James
Copland, M.
Searle, E.
Somervaille, Tim C P
Spencer, Gary J.
Brooks, N.
Amaral, Fabio M R
Basma, Nasar J
Chadwick, John A
Revell, Bradley
Wingelhofer, Bettina
Maiques-Diaz, Alba
Sinclair, Oliver
Camera, Franncesco
Ciceri, Filippo
Wiseman, D. H.
Pegg, N.
West, W.
Knurowski, T.
Frese, K.
Clegg, K.
Campbell, V. L.
Cavet, James
Copland, M.
Searle, E.
Somervaille, Tim C P
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Date
2023
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Article
Citation
Nicosia L, Spencer GJ, Brooks N, Amaral FMR, Basma NJ, Chadwick JA, et al. Therapeutic targeting of EP300/CBP by bromodomain inhibition in hematologic malignancies. Cancer cell. 2023 Dec 11;41(12):2136-53 e13. PubMed PMID: 37995682. Epub 2023/11/24. eng.