Description
ARV-771 is a BET PROTAC based on E3 ligase von Hippel-Lindau with Kds of 34 nM, 4.7 nM, 8.3 nM, 7.6 nM, 9.6 nM, and 7.6 nM for BRD2(1), BRD2(2), BRD3(1), BRD3(2), BRD4(1) and BRD4(2), respectively.
Uses
ARV-771 is an effective BET degrader of the PROTAC class.
Biological Functions
ARV-771, a von Hippel–Landau (VHL) E3 ligase-based BET PROTAC, is highly active against cellular models of CRPC. ARV-771 in these cells results in rapid BET protein degradation with DC50 (the drug concentration that results in 50% protein degradation) values <1 nM. Interestingly, ARV–771–mediated BET degradation leads to decreased both FL-AR and AR-V7 at the transcript level. In contrast, treating CRPC cells with BET inhibitors leads to the suppression of AR-V7 but not of FL-AR levels. Moreover, ARV-771 causes significantly greater apoptotic cell death than a BET inhibitor. ARV-771 dramatically suppresses the proliferation of castration-resistant prostate cancer models via inducing Von Hippel Lindau (VHL) E3 ligase-mediated degradation of BRDs and inhibiting AR signaling. A subsequent study has demonstrated that ARV-771 can also suppress the proliferation of mantle cell lymphoma cells via increasing the levels of tumour suppressors, including CDKN1A/p21, HEXIM1, and NOXA[1].
Biological Activity
ARV-771 is a potent pan-(bromodomain and extra-terminal) BET degrader, a novel BET-PROTAC (proteolysis-targeting chimera), for BRD2(1), BRD2(2), BRD3(1) The Kd values of , BRD3(2), BRD4(1) and BRD4(2) were 34 nM, 4.7 nM, 8.3 nM, 7.6 nM, 9.6 nM and 7.6 nM, respectively.
target
| Target | Value |
BRD2-BD2
(Cell-free assay) | 4.7 nM(Kd) |
BRD3-BD2
(Cell-free assay) | 7.6 nM(Kd) | td>
BRD4-BD2
(Cell-free assay) | 7.6 nM(Kd) |
BRD3-BD1
(Cell-free assay) | 8.3 nM(Kd) |
BRD4-BD1
(Cell-free assay) | 9.6 nM(Kd) |
References
[1] Yuanfei Deng. “ARV-771 Acts as an Inducer of Cell Cycle Arrest and Apoptosis to Suppress Hepatocellular Carcinoma Progression.” Frontiers in Pharmacology (2022).
