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].

dBET6 is a highly potent, selective and cell-permeable degrader of BET based on PROTAC, with an IC50 of 14 nM, and has antitumor activity.

dBET6 is a highly potent, selective and cell-permeable degrader of BET with an IC50 of 14 nM. dBET6 (100 nM) exhibits antitumor activity against T cell acute lymphoblastic leukemia (T-ALL) lines via degradation of BRD4[1].

dBET6 (7.5 mg/kg, p.o., BID) reduces the leukemic burden in a disseminated mouse model of T-ALL[1].

[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.