| Description |
GSK 525762A is a BET bromodomain inhibitor with IC50 of 32.5-42.5 nM.
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| Related Catalog |
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| Target |
IC50: 32.5-42.5 nM (BET)[1]
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| In Vitro |
GSK 525762A (I-BET 762) shows the highest affinity interaction with BET. GSK 525762A binds to the tandem bromodomains of BET with high affinity (dissociation constant Kd of 50.5-61.3 nM). GSK 525762A displaces, with high efficacy (half-maximum inhibitory concentration IC50 of 32.5-42.5 nM), a tetra-acetylated H4 peptide that had been pre-bound to tandem bromodomains of BET[1]. GSK 525762A has high affinity for BD1/BD2 domain of BRD2/3/4 proteins. GSK 525762A treatment leads to a reduction in the recruitment of all three proteins to chromatin[2]. GSK 525762A inhibits OPM-2 cell proliferation with IC50 of 60.15 nM[3].
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| In Vivo |
The antimyeloma activity of GSK 525762A (I-BET 762) is tested dosed orally in an in vivo systemic xenograft model generated by injecting OPM-2 cells into NOD-SCID mice. Daily oral doses of GSK 525762A up to 10 mg/kg and 30 mg/kg given every other day are well tolerated with no clear impact on body weight compared with vehicle control. The plasma hLC concentration is significantly reduced in mice treated with GSK 525762A[3].
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| Cell Assay |
VCaP, LNCaP, 22RV1, DU145 and PC3 prostate cancer cell lines are seeded in 96-well plates at 2000-10,000 cells/well (optimum density for growth) in a total volume of 100μL media containing 10% FBS. Serially diluted compounds in 100μL media are added to the cells 12hr later. Following 96 hr. incubation, cell viability is assessed by Cell-Titer GLO. The values are normalized and IC50 is calculated using GraphPad Prism software. For long-term colony formation assay, 10,000-50,000 cells/well are seeded in six-well plates and treated with either 100 nM or 500 nM of JQ1 or DMSO. After 12 days cells are fixed with methanol, stained with crystal violet and photographed. For colorimetric assays, the stained wells are treated with 500μL 10% acetic acid and the absorbance is measured at 560nm using a spectrophotometer[2].
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| Animal Admin |
Mice[3] The antimyeloma efficacy of orally administered GSK 525762A is tested in a systemic xenograft myeloma model. For this purpose, sublethally irradiated (200 cGy) NOD/SCID mice age 9 to 11 weeks are given 107 OPM-2 myeloma cells via tail vein injection. On day 15 following inoculation, animals are started on oral treatment with GSK 525762A at escalating doses or vehicle (1% methylcellulose and 0.2% sodium lauryl sulfate), which is continued up to day 83. Specifically, 1 group of mice are treated with vehicle and 4 groups with different dosing schedules of GSK 525762A: 3 mg/kg per day; 10 mg/kg per day; 30 mg/kg on alternate days; and 30 to 20 mg/kg per day (ie, 30 mg/kg per day for 14 days, followed by 2 weeks [days 15 to 31] off treatment [drug is withheld due to a decline in body weight until animals has regained weight], follow by 20 mg/kg per day until termination of the experiment [days 43 to 82]). Blood samples (~70 μL) are removed at 0.5 hours after oral administration of GSK 525762A on day 15 (treatment initiation); days 27, 45, and 82 (3, 10, and 20 to 30 mg/kg once per day groups only); and day 83 (30 mg/kg once every other day group only). The blood is centrifuged to obtain 20 μL plasma and stored at -20°C prior to analysis for GSK 525762A by using a specific liquid chromatography/mass spectrometry/mass spectrometry assay.
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| References |
[1]. Nicodeme E, et al. Suppression of inflammation by a synthetic histone mimic. Nature. 2010 Dec 23;468(7327):1119-23. [2]. Asangani IA, et al. Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature. 2014 Jun 12;510(7504):278-82. [3]. Chaidos A, et al. Potent antimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762. Blood. 2014 Jan 30;123(5):697-705.
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