Reference Detail

Ref Type

Journal Article

PMID

(26552700)

Authors

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 A, Robson S, Kumar U, Parr N, Lee K, Lugo D, Jeffrey P, Taylor S, Vecellio ML, Bountra C, Brennan PE, O'Mahony A, Velichko S, Müller S, Hay D, Daniels DL, Urh M, La Thangue NB, Kouzarides T, Prinjha R, Schwaller J, Knapp S

Title

Generation of a Selective Small Molecule Inhibitor of the CBP/p300 Bromodomain for Leukemia Therapy.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	75	23	2015 Dec 01	5106-5119	Cancer Res

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
I-CBP112	I-CBP112	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
I-CBP112			CBP/p300 inhibitor 13	I-CBP112 is a small molecule that selectively inhibits the bromodomains of CREBBP and EP300, potentially resulting in decreased tumor cell growth (PMID: 26552700, PMID: 27673482).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
KMT2A rearrange	leukemia	predicted - sensitive	I-CBP112 + JQ1	Preclinical	Actionable	In a preclinical study, I-CBP112 sensitized leukemia cells harboring KMT2A fusions to JQ1, resulting in decreased cell growth in culture (PMID: 26552700).	26552700
KMT2A rearrange	leukemia	predicted - sensitive	Doxorubicin + I-CBP112	Preclinical	Actionable	In a preclinical study, I-CBP112 sensitized leukemia cells harboring KMT2A fusions to Doxorubicin, leading to decreased cell growth in culture (PMID: 26552700).	26552700