Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

The histone acetyltransferases CBP/p300 are involved in recurrent leukemia-associated chromosomal translocations and are key regulators of cell growth. Therefore, efforts to generate inhibitors of CBP/p300 are of clinical value. We developed a specific and potent acetyl-lysine competitive protein-protein interaction inhibitor, I-CBP112, that targets the CBP/p300 bromodomains. Exposure of human and mouse leukemic cell lines to I-CBP112 resulted in substantially impaired colony formation and induced cellular differentiation without significant cytotoxicity. I-CBP112 significantly reduced the leukemia-initiating potential of MLL-AF9(+) acute myeloid leukemia cells in a dose-dependent manner in vitro and in vivo. Interestingly, I-CBP112 increased the cytotoxic activity of BET bromodomain inhibitor JQ1 as well as doxorubicin. Collectively, we report the development and preclinical evaluation of a novel, potent inhibitor targeting CBP/p300 bromodomains that impairs aberrant self-renewal of leukemic cells. The synergistic effects of I-CBP112 and current standard therapy (doxorubicin) as well as emerging treatment strategies (BET inhibition) provide new opportunities for combinatorial treatment of leukemia and potentially other cancers.

Original publication

DOI

10.1158/0008-5472.can-15-0236

Type

Journal article

Journal

Cancer research

Publication Date

12/2015

Volume

75

Pages

5106 - 5119

Addresses

Nuffield Department of Clinical Medicine, University of Oxford, Ludwig Institute for Cancer Research (LICR), Roosevelt Drive, Oxford OX3 7DQ, UK.

Keywords

Cell Line, Tumor, Animals, Humans, Mice, Oxazepines, Doxorubicin, Antineoplastic Combined Chemotherapy Protocols, Enzyme Inhibitors, Xenograft Model Antitumor Assays, Amino Acid Sequence, Protein Structure, Tertiary, Drug Synergism, Models, Molecular, Molecular Sequence Data, p300-CBP Transcription Factors, Leukemia, Myeloid, Acute