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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 Cancer research
Vol 75
Issue 23
Date 2015 Dec 01
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 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
I-CBP112 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
RUNX1 - RUNX1T1 leukemia sensitive I-CBP112 + JQ1 Preclinical Actionable In a preclinical study, the combination of I-CBP112 and JQ1 worked synergistically to inhibit growth of leukemia cells harboring a RUNX1-RUNX1T1 (AML1-ETO) fusion in culture (PMID: 26552700) 26552700
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
RUNX1 - RUNX1T1 leukemia sensitive I-CBP112 Preclinical Actionable In a preclinical study, I-CBP112 inhibited clonogenic growth in a leukemia cell line harboring a RUNX1-RUNX1T1 (AML1-ETO) fusion 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
RUNX1 - RUNX1T1 leukemia sensitive Doxorubicin + I-CBP112 Preclinical Actionable In a preclinical study, the combination of I-CBP112 and Doxorubicin worked synergistically to inhibit growth of leukemia cells harboring a RUNX1-RUNX1T1 (AML1-ETO) fusion in culture (PMID: 26552700) 26552700