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|Ref Type||Journal Article|
|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.|
|Date||2015 Dec 01|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|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||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|
|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|