dBET1 is a PROTAC, consisting of a BRD4-ligand JQ-1 linkerd to a cereblon E3 ligase ligand, targeting on BET bromodomain BRD4 with DC50 values of < 100nM and 140nM for degradation of BRD4 protein in MV4-11 cells post 18-hour treatment and in H661 cells post 4-hour treatment. dBET1 exhibited a bell-shaped dose−response curve in the cereblon/PROTAC/BRD4 proximity assay[1]. Treatment with dBET1 resulted a depletion of BRD4 in MV4;11 cells at concentration ranging in 0.1-10μM post 18h and a downregulation of BRD4 by 95 at concentration of 100nM post 2h. Similarly, a dose-dependent degradation of BRD4 could be observed in MM1S cells exposure to dBET1 at concentration ranging in 0.5-10μM post 18-hour treatment. The degradation of BRD4 by treatment with 250nM dBET1 for 2h led a decrease of transcription of BRD2, BRD3, MYC and PIM1 targeted by BRD4, in MV4;11 cells. dBET1 at concentration of 0.25μM, 1μM and 2.5μM caused apoptosis of MV4;11 and DHL4 cells more potently than JQ1 post 24h, which could be marked by cleaved PARP and Caspase-3 at 4h or 8h. Similar increase of apoptosis of primary AML cells could be observed by treatment with 1μM and 10μM dBET1 post 24h. Intraperitoneal administration of 50mg/kg dBET1 daily for 14 days achieved suppression of tumor growth MV4;11 xenograft mice. Decreased leukemic burden in bone marrow could be achieved by 19-day administration. dBET1(R) works as a negative control of dBET1[2].
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