dBET6

A PROTAC that drives BRD4 degradation

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5mg

￥1300.00

1040.00

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10mg

￥2175.00

1740.00

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25mg

￥4200.00

3360.00

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50mg

￥6200.00

4960.00

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100mg

￥9925.00

7940.00

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货号: ajce49680
CAS: 1950634-92-0
别名:
分子式: C42H45ClN8O7S
分子量: 841.37
纯度: >98%
溶解度: DMSO : ≥ 100 mg/mL (118.85 mM);Water : < 0.1 mg/mL (insoluble)
储存: Store at -20°C
库存: 现货

Background

dBET6 is a hybrid compound that drives the selective proteasomal degradation of bromodomain-containing protein 4 (BRD4).¹ It is characterized as a proteolysis-targeting chimera (PROTAC) and contains JQ1, which binds bromo- and extra-terminal (BET) proteins, linked to thalidomide, a ligand for the E3 ubiquitin ligase cereblon.² dBET6 binds to BRD4 (IC₅₀ = 14 nM) and induces its degradation when used at a concentration of 100 nM, leading to a global inhibition of transcription in MOLT-4 T cell acute lymphoblastic leukemia (T-ALL) cells.¹ It also reduces leukemic burden in a MOLT-4 T-ALL mouse xenograft model when administered at a dose of 7.5 mg/kg twice per day.

1.Winter, G.E., Mayer, A., Buckley, D.L., et al.BET bromodomain proteins function as master transcription elongation factors independent of CDK9 recruitmentMol. Cell67(1)5-18(2017) 2.Goracci, L., Desantis, J., Valeri, A., et al.Understanding the metabolism of proteolysis targeting chimeras (PROTACs): The next step toward pharmaceutical applicationsJ. Med. Chem.63(20)11615-11638(2020)

Protocol

Animal experiment:

Mice[1]MOLT4 human T-ALL cells are intravenously injected into NSG mice (2×106 cells/mouse). Luminescence is utilized to monitor engraftment (evident at day 6), at which point mice are randomized into three cohorts that receive dBET6 (7.5 mg/kg BID, n = 8), JQ1 (20 mg/kg QD, n = 9) or vehicle (captisol, n = 9) treatment for 14 days. Survival of all three cohorts is subsequently monitored using hind limb paralysis caused by high femoral leukemic burden as a defined endpoint. SUPT11 human T-ALL cells (mCherry+ and Luciferase+) are intravenously injected into NSG mice (2.52×106 cells/mouse). Luminescence is used to monitor successful engraftment, occurring 10 days after injection. At this point, animals are randomized into three cohorts that receive dBET6 (7.5 mg/kg BID, n = 7), JQ1 (7.5 mg/kg BID, n = 7) or vehicle (captisol, n = 7) treatment for 18 days. Treatment burden is assessed via total body luminescence imaging as well as by bone marrow infiltration by mCherry+ T-ALL cells[1].

参考文献:

[1]. Winter GE, et al. BET Bromodomain Proteins Function as Master Transcription Elongation Factors Independent of CDK9 Recruitment. Mol Cell. 2017 Jul 6;67(1):5-18.e19.