I-CBP112 ( I-CBP-112) is a specific and potent acetyl-lysine competitive protein-protein interaction inhibitor (PPI) with anticancer activity. It inhibits the bromodomain-containing transcription factors CREBBP (CBP) and EP300 with IC50 of 0.142 and 0.625 μM, respectively. It significantly enhances acetylation by p300 at the histone H3K18 and H3K23 sites. I-CBP112 stimulated H3K18ac by ~3-fold, I-CBP112 induced enhances acetylation of these same sites by CBP as well as at H4K5. The EC50's of activation of I-CBP112 on p300- and CBP-mediated H3K18 acetylation are ~2 μM. 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. 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.

Physicochemical Properties

Molecular Formula	C27H36N2O5
Molecular Weight	468.59
Exact Mass	468.262
CAS #	1640282-31-0
Related CAS #	1640282-31-0
PubChem CID	90488984
Appearance	White to off-white solid powder
Density	1.1±0.1 g/cm3
Boiling Point	623.5±55.0 °C at 760 mmHg
Flash Point	330.9±31.5 °C
Vapour Pressure	0.0±1.8 mmHg at 25°C
Index of Refraction	1.547
LogP	3.29
Hydrogen Bond Donor Count	0
Hydrogen Bond Acceptor Count	6
Rotatable Bond Count	7
Heavy Atom Count	34
Complexity	649
Defined Atom Stereocenter Count	1
SMILES	CCC(=O)N1CCOC2=C(C1)C=C(C=C2OC[C@H]3CCCN(C3)C)C4=CC(=C(C=C4)OC)OC
InChi Key	YKNAKDFZAWQEEO-IBGZPJMESA-N
InChi Code	InChI=1S/C27H36N2O5/c1-5-26(30)29-11-12-33-27-22(17-29)13-21(20-8-9-23(31-3)24(14-20)32-4)15-25(27)34-18-19-7-6-10-28(2)16-19/h8-9,13-15,19H,5-7,10-12,16-18H2,1-4H3/t19-/m0/s1
Chemical Name	1-[7-(3,4-dimethoxyphenyl)-9-[[(3S)-1-methylpiperidin-3-yl]methoxy]-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]propan-1-one
Synonyms	I-CBP 112; I-CBP-112; I-CBP112.
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

ln Vitro	I-CBP112 significantly enhanced the acetylation of p300 at histone H3K18 and H3K23 sites. H3K18ac is stimulated by I-CBP112 about three times, and these same sites also experience increased CBP and H4K5 acetylation. With an EC50 of less than 2 μM, I-CBP112 activates p300 and CBP-mediated H3K18 acetylation [1]. I-CBP112 treatment of human and murine leukemia cell lines significantly reduced colony formation and induced cell differentiation without appearing to be harmful. BioMAP primary cell sets exhibit distinct reactions to cytokine and marker protein production upon exposure to I-CBP112 [2].
ln Vivo	In both vitro and vivo settings, I-CBP112 dramatically decreased the mLL-AF9+ AML cells' capacity to initiate leukemia in a dose-dependent manner. I-CBP112's synergy with both established standard therapies (doxorubicin) and newer approaches to management (BET inhibition) opens up new avenues for the combined treatment of leukemia and possibly other cancers [2].
Animal Protocol	5 μM of I-CBP112 Mice with Leukemic blasts expressing MLL-AF9
References	[1]. Modulation of p300/CBP Acetylation of Nucleosomes by Bromodomain LigandI-CBP112. Biochemistry. 2016 Jul 12;55(27):3727-34. [2]. Generation of a Selective Small Molecule Inhibitor of the CBP/p300 Bromodomain for Leukemia Therapy. Cancer Res. 2015 Dec 1;75(23):5106-19.

Solubility Data

Solubility (In Vitro)

DMSO:≥ 32 mg/mL Water:<1 mg/mL Ethanol:<1 mg/mL

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.34 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.34 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.5 mg/mL (5.34 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.1341 mL	10.6703 mL	21.3406 mL
	5 mM	0.4268 mL	2.1341 mL	4.2681 mL
	10 mM	0.2134 mL	1.0670 mL	2.1341 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.