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.
|Source||Cancer Prev Res (2018). Figure 1. I-BET-762|
|Cell Lines||Female PyMT mice|
|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 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|
|Animal models||LPS-induced endotoxic shock of C57BL/6 mice model|
|Formulation||20% beta-cyclodextrin, 2% DMSO in 0.9% saline|
|Administration||retro-orbital or tail vein injection|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 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 resveratrol of 11.2 mg/kg.
Selective inhibition of CD4+ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors.
Bandukwala HS, et al. Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14532-7. PMID: 22912406.
BET bromodomain inhibition as a therapeutic strategy to target c-Myc.
Delmore JE, et al. Cell. 2011 Sep 16;146(6):904-17. PMID: 21889194.
Suppression of inflammation by a synthetic histone mimic.
Nicodeme E, et al. Nature. 2010 Dec 23;468(7327):1119-23. PMID: 21068722.
|Related Epigenetic Reader Domain Products|
SGC-CBP30 is a potent CREBBP/EP300 inhibitor with IC50 of 21 nM and 38 nM in cell-free assays, respectively.
ARV-771 is a small-molecule pan-BET degrader with Kd values of 4.7, 7.6, 7.6 nM against BRD2, BRD3 and BRD4, respectively.
PLX51107 is a potent and selective BET inhibitor, with Kds of 1.6, 2.1, 1.7, and 5 nM for BD1 and 5.9, 6.2, 6.1, and 120 nM for BD2 of BRD2, BRD3, BRD4, and BRDT, respectively.
|AZD-5153 HNT salt
AZD-5153 HNT salt is a potent, selective and orally available BET/BRD4 bromodomain inhibitor, disrupts BRD4 with an IC50 of 1.7 nM.
BI-7273 is a potent and selective BRD9 inhibitor with IC50s of 19 nM and 117 nM for BRD9 and BRD7, respectively.
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