A hybrid molecule containing (+)-JQ-1 and thalidomide
dBET1 is a potent BRD4 protein degrader based on PROTAC technology with an EC50 of 430 nM.
Treatment with dBET1 down regulates MYC and PIM1 transcription. Degradation of BRD4 by dBET1 is associated with a more potent apoptotic consequence in MV4;11 cell line. Significantly increased apoptosis after only 4 h of dBET1 treatment is enhanced at 8 h. dBET1 also induces a potent and superior inhibitory effect on MV4;11 cell proliferation at 24 hours (measured by ATP content, IC50= 0.14 uM, compare to IC50= 1.1 uM with JQ1)[1].
Administration of dBET1 attenuates tumor progression as determined by serial volumetric measurement, and decreases tumor weight assessed post-mortem. Acute pharmacodynamic degradation of BRD4 is observed four hours after a first or second daily treatment with dBET1 (50 mg/kg IP). A statistically significant destabilization of BRD4, down regulation of MYC and inhibition of proliferation is observed with dBET1 compare to vehicle control in excised tumors. Two weeks of dBET1 is well tolerated by mice without a meaningful effect on weight, white blood count, hematocrit or platelet count[1].
参考文献:
[1]. Winter GE, et al. DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science. 2015 Jun 19;348(6241):1376-81.
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