dBET6 is a selective and cell-permeable degrader of BET based on PROTAC (IC50: 14 nM). It has antitumor activity.

BET:14 nM

dBET6 (100 nM) 通过降解BRD4，展现出对T细胞急性淋巴细胞性白血病（T-ALL）细胞株的抗肿瘤活性。

dBET6 (7.5 mg/kg, p.o., BID) 在分散型T-ALL小鼠模型中降低了白血病负荷。

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 a 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.