I-CBP112
目录号 : GC34078
A p300 and CBP inhibitor
Cas No.:1640282-31-0
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment: | I-CBP112 is dissolved in DMSO and diluted with appropriate medium before use. Cells (6000 KG1a and 13000 LNCaP cells/well) are plated in 96-well flat-bottom plates approximately 24 h prior to drug treatment. After 24 h, 10–20% fetal bovine serum-containing medium is replaced with 2.5% serum medium, and cells are treated with I-CBP112 in 0.18% DMSO; 0.18% DMSO is shown to have negligible cell growth effects under the conditions used in our experiments. After being exposed to I-CBP112 for 66 h, cells are subjected to a final concentration of 0.476% [3H]thymidine per well and allowed to proliferate for an additional 6 h (exposure to I-CBP112 for a total of 72 h). Cells are harvested, and the counts of 3H in each well are taken relative to those treated with vehicle alone to quantify the effect of the ligand on proliferation[1]. |
Animal experiment: | Mice: Leukemic blasts expressing MLL-AF9 are treated in liquid culture with 5 μM of I-CBP112 for 3 days. Control cells are exposed to the corresponding concentration of the DMSO vehicle. Treated cells are then transplanted into sublethally irradiated syngeneic mice via tail vein injection. Upon the development of signs of disease the mice are sacrificed and analysed[2]. |
References: [1]. Zucconi BE, et al. Modulation of p300/CBP Acetylation of Nucleosomes by Bromodomain LigandI-CBP112. Biochemistry. 2016 Jul 12;55(27):3727-34. | |
I-CBP112 is an inhibitor of p300 and CREB-binding protein (CBP) histone acetyltransferases.1 It binds to the p300 and CBP bromodomains (Kds = 167 and 151 nM, respectively) and is selective for p300 and CBP over BRD4, as well as a panel of 104 nuclear receptors and ion channels and a panel of 32 enzymes at 10 ?M. I-CBP112 displaces acetylated histones from CBP in a cell-free assay (IC50 = 170 nM). It reduces colony formation and increases differentiation of primary murine leukemic blasts and delays disease initiation following leukemic blast transplantation into sub-lethally irradiated mice when used at concentrations of 5 and 10 ?M.
1.Picaud, S., Fedorov, O., Thanasopoulou, A., et al.Generation of a selective small molecule inhibitor of the CBP/p300 bromodomain for leukemia therapyCancer Res.75(23)5106-5119(2015)
| Cas No. | 1640282-31-0 | SDF | |
| Canonical SMILES | COC1=C(OC)C=C(C2=CC(OC[C@H]3CCCN(C)C3)=C(OCCN(C(CC)=O)C4)C4=C2)C=C1 | ||
| 分子式 | C27H36N2O5 | 分子量 | 468.59 |
| 溶解度 | DMSO : ≥ 32 mg/mL (68.29 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
||
| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
 |
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 | 1.067 mL | 2.1341 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
CBP/p300 Bromodomain Inhibitor-I-CBP112 Declines Transcription of the Key ABC Transporters and Sensitizes Cancer Cells to Chemotherapy Drugs
Cancers (Basel) 2021 Sep 14;13(18):4614.PMID:34572840DOI:10.3390/cancers13184614.
The high expression of some ATP-binding cassette (ABC) transporters is linked to multidrug resistance in cancer cells. We aimed to determine if I-CBP112, which is a CBP/p300 bromodomain inhibitor, altered the vulnerability of the MDA-MB-231 cell line to chemotherapy drugs, which are used in neoadjuvant therapy in patients with triple negative breast cancer (TNBC). MDA-MB-231 cells represent TNBC, which is negative for the expression of estrogen and progesterone receptors and HER2 protein. An I-CBP112-induced decrease in the expression of all the studied ABCs in the breast, but also in the lung (A549), and hepatic (HepG2) cancer cell lines was associated with increased accumulation of doxorubicin, daunorubicin, and methotrexate inside the cells as well as with considerable cell sensitization to a wide range of chemotherapeutics. Gene promoters repressed by I-CBP112 in MDA-MB-231 cells, such as ABCC1 and ABCC10, were characterized by enhanced nucleosome acetylation and, simultaneously, by considerably lower trimethylation in the transcription-promoting form of H3K4me3. The CBP/p300 bromodomain inhibitor induced the recruitment of LSD1 to the gene promoters. The inhibition of this demethylase in the presence of I-CBP112 prevented the repression of ABCC1 and ABCC10 and, to a considerable extent, cancer cells' sensitization to drugs. In conclusion, the CBP/p300 bromodomain inhibitor I-CBP112 can be considered as a potent anti-multidrug-resistance agent, capable of repressing key ABC transporters responsible for drug efflux in various cancer types.
Polydatin and I-CBP112 protects early bovine embryo against nicotinamide-induced mitochondrial dysfunction
Theriogenology 2019 Aug;134:1-10.PMID:31108431DOI:10.1016/j.theriogenology.2019.05.007.
The mammalian Sirtuin family of seven enzymes, members of the NAD+-dependent histone deacetylase family that modify histones via direct deacetylation, is involved in the regulation of many antioxidant and oxidative stresses. In the present study, we explored the effects of nicotinamide (NAM)-induced oxidative stress on the in vitro development of bovine embryos, on the acetylation of histone H3 lysine 56 (H3K56ac) and on expression of apoptosis-related genes. Treatment with NAM (10, 20 or 40 mM for 24, 48 or 196 h) during IVC resulted in significantly decreased blastocyst formation (24 h: 38.8 vs. 33.1, 27.3 and 10.2%, with P > 0.05, P < 0.05 and P < 0.01, respectively; 48 h: 37.5 vs. 28.2, 13.4 and 0%, with P < 0.05 and P < 0.01, respectively; 196 h: 35.8 vs. 23.4, 0 and 0%, with P < 0.05, respectively). Treatment with NAM (20 and 40 mM for 24 h) resulted in increased intracellular reactive oxygen species (ROS) levels in 2-cell and blastocysts, and apoptotic cell numbers in blastocysts and decreased mitochondrial membrane potential (ΔΨ) in 2-cell embryos (P < 0.05). Polydatin (PD) and I-CBP112 rescued the 20 mM NAM-induced embryo developmental defects and reduced ROS levels and apoptotic cell numbers in blastocysts (P < 0.05). The gene expression of NF-κB, COX2 and p53 was significantly increased in the NAM-treated group. Immunofluorescence analysis confirmed that the protein levels of nuclear factor-kappa B (NF-κB) decreased significantly after PD and I-CBP112 treatment compared with the control (P < 0.05). High level of H3K56ac induced by NAM was decreased after PD and I-CBP112 treatment (P < 0.05). These findings suggest that NAM treatment induces high levels of H3K56 acetylation that may be involved in oxidative stress-induced bovine developmental defects, which can be tolerated by PD and I-CBP112 treatment.
Modulation of p300/CBP Acetylation of Nucleosomes by Bromodomain Ligand I-CBP112
Biochemistry 2016 Jul 12;55(27):3727-34.PMID:27332697DOI:10.1021/acs.biochem.6b00480.
The histone acetyltransferase (HAT) enzymes p300 and CBP are closely related paralogs that serve as transcriptional coactivators and have been found to be dysregulated in cancer and other diseases. p300/CBP is a multidomain protein and possesses a highly conserved bromodomain that has been shown to bind acetylated Lys residues in both proteins and various small molecules, including I-CBP112 and CBP30. Here we show that the ligand I-CBP112 can stimulate nucleosome acetylation up to 3-fold while CBP30 does not. Activation of p300/CBP by I-CBP112 is not observed with the isolated histone H3 substrate but requires a nucleosome substrate. I-CBP112 does not impact nucleosome acetylation by the isolated p300 HAT domain, and the effects of I-CBP112 on p300/CBP can be neutralized by CBP30, suggesting that I-CBP112 likely allosterically activates p300/CBP through bromodomain interactions. Using mass spectrometry and Western blots, we have found that I-CBP112 particularly stimulates acetylation of Lys18 of histone H3 (H3K18) in nucleosomes, an established in vivo site of p300/CBP. In addition, we show that I-CBP112 enhances H3K18 acetylation in acute leukemia and prostate cancer cells in a concentration range commensurate with its antiproliferative effects. Our findings extend the known pharmacology of bromodomain ligands in the regulation of p300/CBP and suggest a novel approach to modulating histone acetylation in cancer.
Nicotinamide-induced mouse embryo developmental defect rescued by resveratrol and I-CBP112
Mol Reprod Dev 2020 Sep;87(9):1009-1017.PMID:32818292DOI:10.1002/mrd.23405.
Cell cycle of mouse embryo could be delayed by nicotinamide (NAM). Histone H3 lysine 56 (H3K56ac) acetylation plays an important role in mammalian genomic stability and the function of this modification in mouse embryos is not known. Hence, we designed to study the effects of NAM-induced oxidative stress on the developmental ability of mouse embryos, on the acetylation of H3K56ac and the possible functions of this modification related to mouse embryo development. Treatment with NAM (10, 20, or 40 mmol/L for 24 or 48 hr) during in vitro culture significantly decreased developmental rate of blastocyst (24 hr: 90.2 vs. 81.2, 43.2, and 18.2, with p > .05, p < .01, respectively; 48 hr: 89.3 vs. 53.2%, 12.1%, and 0% with p < .05, respectively). NAM treatment (20 mmol/L) for 6 and 31 hr resulted in increased intracellular reactive oxygen species levels in two-cell embryos, and apoptotic cell numbers in blastocysts. Resveratrol (RSV) and I-CBP112 rescued the 20 mmol/L NAM-induced embryo developmental defects. RSV and I-CBP112 increased the level of Sirt1 and decreased the level of H3K56ac induced by NAM in two-cell embryos (p < .05). These data suggest that NAM treatment decreases the expression of Sirt1, which induces high levels of H3K56 acetylation that may be involved in oxidative stress-induced mouse embryo defects, which can be rescued by RSV and I-CBP112.
Combination Targeting of the Bromodomain and Acetyltransferase Active Site of p300/CBP
Biochemistry 2019 Apr 23;58(16):2133-2143.PMID:30924641DOI:10.1021/acs.biochem.9b00160.
p300 and CBP are highly related histone acetyltransferase (HAT) enzymes that regulate gene expression, and their dysregulation has been linked to cancer and other diseases. p300/CBP is composed of a number of domains including a HAT domain, which is inhibited by the small molecule A-485, and an acetyl-lysine binding bromodomain, which was recently found to be selectively antagonized by the small molecule I-CBP112. Here we show that the combination of I-CBP112 and A-485 can synergize to inhibit prostate cancer cell proliferation. We find that the combination confers a dramatic reduction in p300 chromatin occupancy compared to the individual effects of blocking either domain alone. Accompanying this loss of p300 on chromatin, combination treatment leads to the reduction of specific mRNAs including androgen-dependent and pro-oncogenic prostate genes such as KLK3 (PSA) and c-Myc. Consistent with p300 directly affecting gene expression, mRNAs that are significantly reduced by combination treatment also exhibit a strong reduction in p300 chromatin occupancy at their gene promoters. The relatively few mRNAs that are up-regulated upon combination treatment show no correlation with p300 occupancy. These studies provide support for the pharmacologic advantage of concurrent targeting of two domains within one key epigenetic modification enzyme.