ARV-771

产品活性：ARV-771 是 PROTAC 类的有效的 BET 降解剂。对 BRD2, BRD3 和 BRD4 的 K_d 值分别为 4.7, 7.6 和 7.6 nM。

研究领域：Epigenetics  |  PROTAC

作用靶点：Epigenetic Reader Domain  |  PROTAC

In Vitro: ARV-771, a small-molecule pan-BET degrader based on proteolysis-targeting chimera (PROTAC) technology, demonstrates dramatically improved efficacy in cellular models of CRPC as compared with BET inhibition. ARV-771 potently degrades BRD2/3/4 in 22Rv1 cells with a DC₅₀ less than 5 nM. c-MYC protein is a downstream effector of BET proteins. Treatment with ARV-771 results in depletion of c-MYC with an IC₅₀ of less than 1 nM. ARV-771 shows strong antiproliferative effect on 22Rv1, VCaP, and LnCaP95 cell lines. ARV-771 treatment has a pronounced effect on cell morphology consistent with apoptosis. FL-AR and AR-V7 mRNA are down-regulated upon treatment with 10 nM ARV-771 in VCaP cells. ARV-771 has an antiandrogenic effect on a number of AR-regulated genes in VCaP cells.

In Vivo: Treatment of non castrated male Nu/Nu mice bearing AR-V7+ 22Rv1 tumor xenografts with daily subcutaneous injections of ARV-771 at 10 mg/kg for 3 d results in 37% and 76% down-regulation of BRD4 and c-MYC levels, respectively, in tumor tissue. A marked down-regulation in levels of AR-V7 is observed in the 22Rv1 tumors after ARV-771 treatment.

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