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Generation of a Selective Small Molecule Inhibitor of the CBP/p300 Bromodomain for Leukemia Therapy
Sarah Picaud1,2, Oleg Fedorov1,3, Angeliki Thanasopoulou4
1Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
Abstract:
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.
Insights
A new inhibitor, I-CBP112, targets CBP/p300 bromodomains to impair leukemia cell growth and promote differentiation. It shows promise in combination therapies for leukemia and other cancers.
Area of Science:
- Epigenetics
- Cancer Biology
- Drug Discovery
Background:
- Histone acetyltransferases CBP/p300 are implicated in leukemia development through chromosomal translocations.
- CBP/p300 are crucial regulators of cellular growth, making them attractive therapeutic targets.
Purpose of the Study:
- To develop and evaluate a novel inhibitor targeting CBP/p300 bromodomains for leukemia treatment.
- To assess the efficacy of I-CBP112 in preclinical leukemia models.
Main Methods:
- Development of I-CBP112, a specific acetyl-lysine competitive inhibitor of CBP/p300 bromodomains.
- In vitro and in vivo testing of I-CBP112 on human and mouse leukemic cell lines, including MLL-AF9(+) acute myeloid leukemia.
- Evaluation of I-CBP112 in combination with BET bromodomain inhibitor JQ1 and doxorubicin.
Main Results:
- I-CBP112 demonstrated potent inhibition of CBP/p300 bromodomains.
- Treatment with I-CBP112 impaired leukemic cell colony formation and induced differentiation without significant cytotoxicity.
- I-CBP112 dose-dependently reduced leukemia-initiating potential in vitro and in vivo.
- I-CBP112 enhanced the cytotoxicity of JQ1 and doxorubicin.
Conclusions:
- I-CBP112 is a novel, potent inhibitor of CBP/p300 bromodomains that effectively targets leukemic cell self-renewal.
- I-CBP112 exhibits synergistic effects with doxorubicin and BET inhibitors, suggesting potential for combinatorial leukemia therapy.
- This study opens new avenues for treating leukemia and potentially other cancers using CBP/p300-targeted combination strategies.
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