dBET6

dBET6 is a highly cell-permeable degrader of BET bromodomains. It is potent in most cancer cell lines. This compound features highly increased cellular potency with evident degradation in the sub-nanomolar range. Treatment with 100 nM of this chemical leads to degradation of BRD4 after 1 hr, prompting subsequent downregulation of c-MYC and induction of apoptosis. It disrupts global productive transcription elongation. Its treatment leads to a widespread decrease in steady-state mRNA levels, but observed an incommensurate impact on expression of members of the core regulatory circuitry of leukemogenic transcription factors. The collapse of the core transcriptional machinery prompted by BET degradation precedes a robust apoptotic response, of apparent translational significance^[1].

dBET6 is well tolerated. Upon treatment with this compound, a significant reduction of leukemic burden is observed in a disseminated mouse model of T-ALL. Moreover, mice treated with this chemical (7.5 mg/kg BID) exhibits a significant survival benefit compared to mice treated with vehicle control or JQ1 (20 mg/kg QD)^[1].

MOLT4 cells deficient in CRBN expression are treated with various concentrations of either dBET1 or dBET6 for 3 hr. Cells are collected by centrifugation, washed once with PBS and transferred into PCR tubes, spun down and incubated at 47.5°C for 3 min. After a subsequent incubation for 3 min on 25°C, cells are lysed by addition of 30 µL lysis buffer and three repeated freeze-thaw cycles using liquid nitrogen.

• https://pubmed.ncbi.nlm.nih.gov/28673542/