I-BET-762 (GSK525762) is a small molecule inhibitor of the BET (Bromodomain and Extra-Terminal) family of bromodomain-containing proteins. BET inhibitor I-BET-762 binds to the acetylated lysine recognition motifs on the bromodomain of BET proteins, thereby preventing the interaction between the BET proteins and acetylated histone peptides. I-BET-762 (GSK525762) was previously shown to suppress the production of proinflammatory proteins by macrophages and block acute inflammation in mice. Treatment of naive CD4(+) T cells with I-BET-762 during the first 2 d of differentiation had long-lasting effects on subsequent gene expression and cytokine production. The short 2-d treatment with I-BET-762 inhibited the ability of antigen-specific T cells, differentiated under Th1 but not Th17 conditions in vitro, to induce pathogenesis in an adoptive transfer model of experimental autoimmune encephalomyelitis. The suppressive effects of I-BET-762 on T-cell mediated inflammation in vivo were accompanied by decreased recruitment of macrophages, consistent with decreased GM-CSF production by CNS-infiltrating T cells.
JCI Insight. 2022 Sep 8;7(17):e151851.
Targeting ESR1 mutation-induced transcriptional addiction in breast cancer with BET inhibition
I-BET-762 purchased from AbMole
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Source | Cancer Prev Res (2018). Figure 1. I-BET-762 |
| Method | gavaged | |
| Cell Lines | Female PyMT mice | |
| Concentrations | 60 mg/kg | |
| Incubation Time | 48 hrs | |
| Results | Treatment with I-BET 762 significantly (p<0.05) delayed the development of mammary tumors. The average time of the first palpable tumor increased from 13.1±0.8 weeks in the control group to 16.3±1.0 weeks with the I-BET 762 treatment |
| Cell Experiment | |
|---|---|
| Cell lines | isolated CD4+ T cells |
| Preparation method | CD4+ T cells are isolated from lymph nodes and spleens of 10- to 12-wk-old 2D2 transgenic mice by using Invitrogen Dynal Beads according to manufacturer’s protocols. The isolated CD4+ T cells were stimulated with platebound anti-CD3 and anti-CD28 antibodies alone (ThN conditions), or in the presence of anti-IL4 and IL-12 (Th1 conditions), IL-4 and anti-IL12 (Th2 conditions), IL-1β, IL-6, and IL-23 (Th17 conditions), or TGF-β (Treg conditions). Along with the cytokine mixtures were included either the Control-768 (GSK525768A) or I-BET-762 (GSK525762A) compounds. The cells are stimulated in these condition for 60–72 h and then harvested and expanded with DMEM media containing 10% (vol/vol) FBS, antibiotics, Lglutamine, and B-2ME. The cells were counted and reset to 0.5 × 106 cells per mL on days 3 and 4 after initial stimulation. Over the course of 5 d of T-cell culture and expansion, the compounds were diluted 12-fold relative to the starting concentrations. In case of Th1, Th2, and iTreg conditions, IL-2 was added to the media at a final concentration of 20 units per mL. On day 5 after initial activation, the cells were harvested and restimulated with PMA (10 nM) and ionomycin (1 μM) for 6 h. Brefeldin A (10 μg/mL) was added during the last 2 h of stimulation. Subsequently, the cells were fixed with 4% (wt/vol) paraformaldehyde in PBS for 15 min at 25 °C, washed in PBS, and permeabilized in saponin buffer [PBS, 0.5% saponin (Sigma), 1% (wt/vol) BSA, and 0.1% (wt/vol) sodium azide]. Intracellular staining was performed as described for indicated cytokines. In some experiments, cell surface staining was completed before fixation. |
| Concentrations | 125, 250, 500nM |
| Incubation time | 60-72h |
| Animal Experiment | |
|---|---|
| Animal models | LPS-induced endotoxic shock of C57BL/6 mice model |
| Formulation | 20% beta-cyclodextrin, 2% DMSO in 0.9% saline |
| Dosages | 30 mg/kg |
| Administration | retro-orbital or tail vein injection |
| Molecular Weight | 423.9 |
| Formula | C22H22ClN5O2 |
| CAS Number | 1260907-17-2 |
| Solubility (25°C) | DMSO |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
[2] Delmore JE, et al. Cell. BET bromodomain inhibition as a therapeutic strategy to target c-Myc.
[3] Nicodeme E, et al. Nature. Suppression of inflammation by a synthetic histone mimic.
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