Background
ARV-771 is a proteolysis-targeting chimera (PROTAC) that drives the degradation of bromodomain and extra terminal domain (BET) family proteins.1 It is comprised of a BET-binding moiety conjugated via a linker to a von Hippel-Lindau (VHL) E3 ligase-binding moiety. ARV-771 induces degradation of bromodomain-containing protein 2 (BRD2), BRD3, and BRD4 in 22Rv1 castration-resistant prostate cancer (CRPC) cells with half-maximal degradation (DC50) values of less than 5 nM for all. It inhibits proliferation of and increases poly(ADP-ribose) polymerase (PARP) cleavage in 22Rv1 cells in a concentration-dependent manner. ARV-771 reduces full-length androgen receptor protein levels and prevents increases in ERG induced by the synthetic androgen R1881 in VCaP cells in a concentration-dependent manner. ARV-771 (30 mg/kg per day, s.c.) induces tumor regression in a 22Rv1 mouse xenograft model.
1.Raina, K., Lu, J., Qian, Y., et al.PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancerProc. Natl. Acad. Sci. USA113(26)7124-7129(2016)
Protocol
Cell experiment: | ARV-771 is dissolved in DMSO. 22Rv1 cells (5,000 cells per well) are dosed with ARV-771 serially diluted 1:3 for a 10-point dose curve for 72 h. CellTiter-Glo Luminescent Cell Viability Assay is added, and the plate is read on a luminometer. Data are analyzed and plotted using GraphPad Prism software[1]. |
Animal experiment: | Mice: Mice bearing tumors are treated with ARV-771 (5, 10, 30, 50 mg/kg) for up to 3 wk, depending on the experiment. Mice are sacrificed 8 h after the final dose. Plasma and tissues are harvested and flash frozen for further analysis[1]. |
参考文献: [1]. Raina K, et al. PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer. Proc Natl Acad Sci U S A. 2016 Jun 28;113(26):7124-9. |
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