Generation of a selective small molecule inhibitor of the CBP/p300 bromodomain for Leukemia therapy. Picaud, S., Fedorov, O., Thanasopoulou, A., Leonards, K., Jones, K., Meier, J., Olzscha, H., Monteiro, O., Martin, S., Philpott, M., Tumber, A., Filippakopoulos, P., Yapp, C., Wells, C., Che, K., H., Bannister, A., Robson, S., Kumar, U., Parr, N., Lee, K., Lugo, D., Jeffrey, P., Taylor, S., Vecellio, M., L., Bountra, C., Brennan, P., E., O'Mahony, A., Velichko, S., Muller, S., Hay, D., Daniels, D., L., Urh, M., La Thangue, N., B., Kouzarides, T., Prinjha, R., Schwaller, J., & Knapp, S. Cancer Research, 75(23):5106-5119, 11, 2015. ![Generation of a selective small molecule inhibitor of the CBP/p300 bromodomain for Leukemia therapy [link]](https://bibbase.org/img/filetypes/link.svg "link")
Website doi abstract bibtex 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+ AML 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.
@article{
title = {Generation of a selective small molecule inhibitor of the CBP/p300 bromodomain for Leukemia therapy},
type = {article},
year = {2015},
pages = {5106-5119},
volume = {75},
websites = {http://www.ncbi.nlm.nih.gov/pubmed/26552700},
month = {11},
day = {9},
id = {7a51ada6-9104-367f-aab9-8a7df3fba6f9},
created = {2015-11-18T16:40:02.000Z},
accessed = {2015-11-12},
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last_modified = {2018-07-09T12:39:49.927Z},
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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+ AML 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.},
bibtype = {article},
author = {Picaud, Sarah and Fedorov, Oleg and Thanasopoulou, Angeliki and Leonards, Katharina and Jones, Katherine and Meier, Julia and Olzscha, Heidi and Monteiro, Octovia and Martin, Sarah and Philpott, Martin and Tumber, Anthony and Filippakopoulos, Panagis and Yapp, Clarence and Wells, Christopher and Che, Ka Hing and Bannister, Andrew and Robson, Samuel and Kumar, Umesh and Parr, Nigel and Lee, Kevin and Lugo, Dave and Jeffrey, Philip and Taylor, Simon and Vecellio, Matteo L. and Bountra, Chas and Brennan, Paul E. and O'Mahony, Alison and Velichko, Sharlene and Muller, Susanne and Hay, Duncan and Daniels, Danette L. and Urh, Marjeta and La Thangue, Nicholas B. and Kouzarides, Tony and Prinjha, Rab and Schwaller, Jurg and Knapp, Stefan},
doi = {10.1158/0008-5472.CAN-15-0236},
journal = {Cancer Research},
number = {23}
}
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