Generation of a selective small molecule inhibitor of the CBP/p300 bromodomain for leukemia therapy

S. Picaud; O. Fedorov; A. Thanasopoulou; K. Leonards; K. Jones; J. Meier; H. Olzscha; O. Monteiro; S. Martin; M. Philpott; A. Tumber; P. Filippakopoulos; C. Yapp; C. Wells; Ka Hing Che; Andrew J. Bannister; S. Robson; U. Kumar; N. Parr; H. K. Lee; D. Lugo; P. Jeffrey; Rod S. Taylor; M. L. Vecellio; C. Bountra; P. E. Brennan; A. O'Mahony; S. Velichko; S. Muller; D. Hay; D. L. Daniels; M. Urh; N. B. La Thangue; Tony Kouzarides; Rab K. Prinjha; J. Schwaller; S. Knapp

doi:10.1158/0008-5472.CAN-15-0236

Generation of a selective small molecule inhibitor of the CBP/p300 bromodomain for leukemia therapy

S. Picaud, O. Fedorov, A. Thanasopoulou, K. Leonards, K. Jones, J. Meier, H. Olzscha, O. Monteiro, S. Martin, M. Philpott, A. Tumber, P. Filippakopoulos, C. Yapp, C. Wells, Ka Hing Che, Andrew J. Bannister, S. Robson, U. Kumar, N. Parr, H. K. LeeD. Lugo, P. Jeffrey, Rod S. Taylor, M. L. Vecellio, C. Bountra, P. E. Brennan, A. O'Mahony, S. Velichko, S. Muller, D. Hay, D. L. Daniels, M. Urh, N. B. La Thangue, Tony Kouzarides, Rab K. Prinjha, J. Schwaller, S. Knapp

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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+ 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 language	English
Pages (from-to)	5106-5119
Number of pages	14
Journal	Cancer Research
Volume	75
Issue number	23
Early online date	9 Nov 2015
DOIs	https://doi.org/10.1158/0008-5472.CAN-15-0236
Publication status	Published - 1 Dec 2015
Externally published	Yes

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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. J., Robson, S., Kumar, U., Parr, N., ... Knapp, S. (2015). Generation of a selective small molecule inhibitor of the CBP/p300 bromodomain for leukemia therapy. Cancer Research, 75(23), 5106-5119. https://doi.org/10.1158/0008-5472.CAN-15-0236

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title = "Generation of a selective small molecule inhibitor of the CBP/p300 bromodomain for leukemia therapy",

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. ",

author = "S. Picaud and O. Fedorov and A. Thanasopoulou and K. Leonards and K. Jones and J. Meier and H. Olzscha and O. Monteiro and S. Martin and M. Philpott and A. Tumber and P. Filippakopoulos and C. Yapp and C. Wells and Che, \{Ka Hing\} and Bannister, \{Andrew J.\} and S. Robson and U. Kumar and N. Parr and Lee, \{H. K.\} and D. Lugo and P. Jeffrey and Taylor, \{Rod S.\} and Vecellio, \{M. L.\} and C. Bountra and Brennan, \{P. E.\} and A. O'Mahony and S. Velichko and S. Muller and D. Hay and Daniels, \{D. L.\} and M. Urh and \{La Thangue\}, \{N. B.\} and Tony Kouzarides and Prinjha, \{Rab K.\} and J. Schwaller and S. Knapp",

year = "2015",

month = dec,

day = "1",

doi = "10.1158/0008-5472.CAN-15-0236",

language = "English",

volume = "75",

pages = "5106--5119",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "23",

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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, KH, Bannister, AJ, Robson, S, Kumar, U, Parr, N, Lee, HK, Lugo, D, Jeffrey, P, Taylor, RS, Vecellio, ML, Bountra, C, Brennan, PE, O'Mahony, A, Velichko, S, Muller, S, Hay, D, Daniels, DL, Urh, M, La Thangue, NB, Kouzarides, T, Prinjha, RK, Schwaller, J & Knapp, S 2015, 'Generation of a selective small molecule inhibitor of the CBP/p300 bromodomain for leukemia therapy', Cancer Research, vol. 75, no. 23, pp. 5106-5119. https://doi.org/10.1158/0008-5472.CAN-15-0236

TY - JOUR

T1 - Generation of a selective small molecule inhibitor of the CBP/p300 bromodomain for leukemia therapy

AU - Picaud, S.

AU - Fedorov, O.

AU - Thanasopoulou, A.

AU - Leonards, K.

AU - Jones, K.

AU - Meier, J.

AU - Olzscha, H.

AU - Monteiro, O.

AU - Martin, S.

AU - Philpott, M.

AU - Tumber, A.

AU - Filippakopoulos, P.

AU - Yapp, C.

AU - Wells, C.

AU - Che, Ka Hing

AU - Bannister, Andrew J.

AU - Robson, S.

AU - Kumar, U.

AU - Parr, N.

AU - Lee, H. K.

AU - Lugo, D.

AU - Jeffrey, P.

AU - Taylor, Rod S.

AU - Vecellio, M. L.

AU - Bountra, C.

AU - Brennan, P. E.

AU - O'Mahony, A.

AU - Velichko, S.

AU - Muller, S.

AU - Hay, D.

AU - Daniels, D. L.

AU - Urh, M.

AU - La Thangue, N. B.

AU - Kouzarides, Tony

AU - Prinjha, Rab K.

AU - Schwaller, J.

AU - Knapp, S.

PY - 2015/12/1

Y1 - 2015/12/1

N2 - 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.

AB - 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.

U2 - 10.1158/0008-5472.CAN-15-0236

DO - 10.1158/0008-5472.CAN-15-0236

M3 - Article

SN - 0008-5472

VL - 75

SP - 5106

EP - 5119

JO - Cancer Research

JF - Cancer Research

IS - 23

ER -

Generation of a selective small molecule inhibitor of the CBP/p300 bromodomain for leukemia therapy

Abstract

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