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Chemical Structure| 1260907-17-2 同义名 : I-BET-762; GSK525762; GSK525762A; I-BET762
CAS号 : 1260907-17-2
货号 : A222643
分子式 : C22H22ClN5O2
纯度 : 99%+
分子量 : 423.9
MDL号 : MFCD22417091
存储条件：

Pure form Sealed in dry, 2-8°C

In solvent -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 190 mg/mL(448.22 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO

1M HCl: 100 mg/mL(235.91 mM)，配合低频超声，并调节pH至1
生物活性
靶点

  • BET

    BET proteins, IC50:35 nM
描述 The Bromodomain and Extra-Terminal Domain BET (Bromodomain and Extra-Terminal Domain) family is characterized by the presence of two tandem bromodomains and an extra-terminal domain. BET proteins can govern the assembly of histone acetylation-dependent chromatin complexes, thus regulating gene expression. I-BET-762 is a highly selective BET protein inhibitor with IC50 values of 32.5–42.5nM (measured by FRET analysis). I-BET-762 can suppress the inflammatory gene expression, including LPS-inducible Il6, Ifnb1, Il1b, Il12a, Cxcl9, Ccl12 and IL-1b processing enzyme Mefv, as well as diminish expression of transcription factors Rel, Irf4 and Irf8 in BMDMs. In contrast, I-BET762 only has a marginal effect on general gene transcription in macrophages without LPS-stimulation. Injection of I-BET-762, 30mg/kg, i.v., 1h before or 1.5 h after LPS administration can attenuate death of mice. Twice-daily injections of I-BET-762, 30mg/kg, i.v., for 2 days protected mice against death caused by sepsis[1]. A phase 1 study of I-BET762 in combination with androgen deprivation therapy treatment for castrate-resistant prostate cancer and a phase 2 study of I-BET762 in combination with Fulvestrant treatment for ER+ breast cancer is recruiting (see https://clinicaltrials.gov/).
作用机制 I-BET-762 can interact with the BRD pocket in the manner of competition with acetylated peptide binding and displace BET proteins from acetylated chromatin in cells.
细胞研究
细胞系 浓度 检测类型 检测时间 活性说明 数据源
Rosetta2 DE3 cells Function assay 30 mins Displacement of FAM-labeled ZBA248 from BRD3 BD2 (306 to 417 amino acid residues) (unknown origin) expressed in Rosetta2 DE3 cells after 30 mins by fluorescence polarization assay, Ki=30.3 nM 26080064
临床研究
NCT号 适应症或疾病 临床期 招募状态 预计完成时间 地点
NCT03702036 - - - -
NCT02706535 Drug Interactions Phase 1 Completed - United States, Maryland ... 展开 >> GSK Investigational Site Baltimore, Maryland, United States, 21225 收起 <<
NCT03266159 Solid Tumours Phase 2 Withdrawn(Study withdrawn befo... 展开 >>re active to fully evaluate impact of changing practice in target population.) 收起 << August 19, 2020 -
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.36mL

0.47mL

0.24mL

11.80mL

2.36mL

1.18mL

23.59mL

4.72mL

2.36mL
参考文献

[1]Wyce A, Degenhardt Y, et al. Inhibition of BET bromodomain proteins as a therapeutic approach in prostate cancer. Oncotarget. 2013 Dec;4(12):2419-29.

[2]Chan CH, Fang C, et al. BET bromodomain inhibition suppresses transcriptional responses to cytokine-Jak-STAT signaling in a gene-specific manner in human monocytes. Eur J Immunol. 2015 Jan;45(1):287-297.

[3]Small molecule inhibitors of the BET family: Selective inhibition of the N-terminal bromodomain