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

• Published in: Cancer cell 2023-12, Vol.41 (12), p.2136-2153.e13
• Main Authors: Nicosia, Luciano, Spencer, Gary J, Brooks, Nigel, Amaral, Fabio M R, Basma, Naseer J, Chadwick, John A, Revell, Bradley, Wingelhofer, Bettina, Maiques-Diaz, Alba, Sinclair, Oliver, Camera, Francesco, Ciceri, Filippo, Wiseman, Daniel H, Pegg, Neil, West, Will, Knurowski, Tomasz, Frese, Kris, Clegg, Karen, Campbell, Victoria L, Cavet, James, Copland, Mhairi, Searle, Emma, Somervaille, Tim C P
• Format: Article
• Language: English
• Subjects: Cell Line, Tumor; E1A-Associated p300 Protein; Hematologic Neoplasms - drug therapy; Hematologic Neoplasms - genetics; Humans; Nuclear Proteins; Protein Domains; Transcription Factors
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2023.11.001

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.