Name: ARV-771
Brand: BOC Sciences
Price: 439 USD
Availability: MadeToOrder

Purity

≥95%

Solubility

Soluble in DMSO

Appearance

Off-white Solid

Storage

Store at -20°C

Shipping

Room temperature in continental US; may vary elsewhere.

IUPACName

(2S,4R)-1-[(2S)-2-[[2-[3-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]propoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

Synonyms

ARV 771; ARV771; (2S,4R)-1-((S)-2-(tert-butyl)-15-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-4,14-dioxo-6,10-dioxa-3,13-diazapentadecanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; L-Prolinamide, N-[2-[3-[2-[[2-[(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetyl]amino]ethoxy]propoxy]acetyl]-3-methyl-L-valyl-4-hydroxy-N-[(1S)-1-[4-(4-methyl-5-thiazolyl)phenyl]ethyl]-, (4R)-; N-({3-[2-({[(6S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetyl}amino)ethoxy]propoxy}acetyl)-3-methyl-L-valyl-(4R)-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide

Density

1.39±0.1 g/cm3

InChI Key

PQOGZKGXGLHDGS-QQRWPDCKSA-N

InChI

InChI=1S/C49H60ClN9O7S2/c1-27-30(4)68-48-41(27)42(33-14-16-35(50)17-15-33)54-37(45-57-56-31(5)59(45)48)23-39(61)51-18-21-65-19-9-20-66-25-40(62)55-44(49(6,7)8)47(64)58-24-36(60)22-38(58)46(63)53-28(2)32-10-12-34(13-11-32)43-29(3)52-26-67-43/h10-17,26,28,36-38,44,60H,9,18-25H2,1-8H3,(H,51,61)(H,53,63)(H,55,62)/t28-,36+,37-,38-,44+/m0/s1

SMILES

O=C(NC(C(=O)N1CC(O)CC1C(=O)NC(C=2C=CC(=CC2)C=3SC=NC3C)C)C(C)(C)C)COCCCOCCNC(=O)CC4N=C(C=5C=CC(Cl)=CC5)C6=C(SC(=C6C)C)N7C(=NN=C74)C

Pub Chem ID

126619980

Mechanism

Target: ARV-771 targets BET bromodomain proteins, including BRD2, BRD3, and BRD4.

Binding site: Its BET ligand binds acetyl-lysine recognition pockets within BET bromodomains.

Mechanism of action: ARV-771 is a VHL-recruiting BET PROTAC designed to induce potent degradation of BET family chromatin readers. The molecule couples a BET bromodomain ligand to a von Hippel-Lindau ligand, enabling formation of BET–PROTAC–VHL ternary complexes and subsequent ubiquitination of BRD2, BRD3, and BRD4. Proteasomal depletion of these transcriptional regulators enables sustained disruption of BET-dependent gene-expression programs. ARV-771 is widely used for studying chromatin reader dependency, MYC-associated transcriptional regulation, BET paralog degradation, pathway suppression, and degradation-specific phenotypes compared with reversible bromodomain inhibition.

Applications

• PROTAC-Mediated Degradation of BET Proteins: ARV-771 is utilized in research to selectively degrade BET family proteins, such as BRD2, BRD3, and BRD4, through the ubiquitin-proteasome system. This targeted degradation helps elucidate the role of BET proteins in transcriptional regulation and their potential as therapeutic targets in various cancers.

• Targeted Degradation in Oncology Research: Researchers employ ARV-771 to explore the effects of degrading oncogenic proteins, providing insights into cancer biology and potential therapeutic interventions. By removing specific proteins implicated in tumorigenesis, ARV-771 facilitates the study of cellular pathways and mechanisms driving cancer progression.

• Mechanistic Studies of Protein Degradation: ARV-771 serves as a tool for investigating the mechanistic aspects of PROTAC-induced protein degradation. It aids in understanding the kinetics and dynamics of the degradation process, offering valuable data on the efficiency and specificity of targeted protein degradation strategies.

• Epigenetic Modulation via PROTACs: By degrading key epigenetic regulators, ARV-771 assists in the study of chromatin remodeling and gene expression changes. This application is crucial for deciphering the complex interactions within epigenetic landscapes and their implications in diseases characterized by dysregulated gene expression.

1.PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer.

Raina K;Lu J;Qian Y;Altieri M;Gordon D;Rossi AM;Wang J;Chen X;Dong H;Siu K;Winkler JD;Crew AP;Crews CM;Coleman KG Proc Natl Acad Sci U S A. 2016 Jun 28;113(26):7124-9. doi: 10.1073/pnas.1521738113. Epub 2016 Jun 6.

Prostate cancer has the second highest incidence among cancers in men worldwide and is the second leading cause of cancer deaths of men in the United States. Although androgen deprivation can initially lead to remission, the disease often progresses to castration-resistant prostate cancer (CRPC), which is still reliant on androgen receptor (AR) signaling and is associated with a poor prognosis. Some success against CRPC has been achieved by drugs that target AR signaling, but secondary resistance invariably emerges, and new therapies are urgently needed. Recently, inhibitors of bromodomain and extra-terminal (BET) family proteins have shown growth-inhibitory activity in preclinical models of CRPC. Here, we demonstrate that 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. Unlike BET inhibitors, ARV-771 results in suppression of both AR signaling and AR levels and leads to tumor regression in a CRPC mouse xenograft model. This study is, to our knowledge, the first to demonstrate efficacy with a small-molecule BET degrader in a solid-tumor malignancy and potentially represents an important therapeutic advance in the treatment of CRPC.

2.BET protein proteolysis targeting chimera (PROTAC) exerts potent lethal activity against mantle cell lymphoma cells.

Sun B;Fiskus W;Qian Y;Rajapakshe K;Raina K;Coleman KG;Crew AP;Shen A;Saenz DT;Mill CP;Nowak AJ;Jain N;Zhang L;Wang M;Khoury JD;Coarfa C;Crews CM;Bhalla KN Leukemia. 2018 Feb;32(2):343-352. doi: 10.1038/leu.2017.207. Epub 2017 Jun 30.

Bromodomain extraterminal protein (BETP) inhibitors transcriptionally repress oncoproteins and nuclear factor-κB (NF-κB) target genes that undermines the growth and survival of mantle cell lymphoma (MCL) cells. However, BET bromodomain inhibitor (BETi) treatment causes accumulation of BETPs, associated with reversible binding and incomplete inhibition of BRD4 that potentially compromises the activity of BETi in MCL cells. Unlike BETi, BET-PROTACs (proteolysis-targeting chimera) ARV-825 and ARV-771 (Arvinas, Inc.) recruit and utilize an E3-ubiquitin ligase to effectively degrade BETPs in MCL cells. BET-PROTACs induce more apoptosis than BETi of MCL cells, including those resistant to ibrutinib. BET-PROTAC treatment induced more perturbations in the mRNA and protein expressions than BETi, with depletion of c-Myc, CDK4, cyclin D1 and the NF-κB transcriptional targets Bcl-xL, XIAP and BTK, while inducing the levels of HEXIM1, NOXA and CDKN1A/p21. Treatment with ARV-771, which possesses superior pharmacological properties compared with ARV-825, inhibited the in vivo growth and induced greater survival improvement than the BETi OTX015 of immune-depleted mice engrafted with MCL cells. Cotreatment of ARV-771 with ibrutinib or the BCL2 antagonist venetoclax or CDK4/6 inhibitor palbociclib synergistically induced apoptosis of MCL cells.

3.Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells.

Saenz DT;Fiskus W;Qian Y;Manshouri T;Rajapakshe K;Raina K;Coleman KG;Crew AP;Shen A;Mill CP;Sun B;Qiu P;Kadia TM;Pemmaraju N;DiNardo C;Kim MS;Nowak AJ;Coarfa C;Crews CM;Verstovsek S;Bhalla KN Leukemia. 2017 Sep;31(9):1951-1961. doi: 10.1038/leu.2016.393. Epub 2017 Feb 2.

The PROTAC (proteolysis-targeting chimera) ARV-825 recruits bromodomain and extraterminal (BET) proteins to the E3 ubiquitin ligase cereblon, leading to degradation of BET proteins, including BRD4. Although the BET-protein inhibitor (BETi) OTX015 caused accumulation of BRD4, treatment with equimolar concentrations of ARV-825 caused sustained and profound depletion (>90%) of BRD4 and induced significantly more apoptosis in cultured and patient-derived (PD) CD34+ post-MPN sAML cells, while relatively sparing the CD34+ normal hematopoietic progenitor cells. RNA-Seq, Reverse Phase Protein Array and mass cytometry 'CyTOF' analyses demonstrated that ARV-825 caused greater perturbations in messenger RNA (mRNA) and protein expressions than OTX015 in sAML cells. Specifically, compared with OTX015, ARV-825 treatment caused more robust and sustained depletion of c-Myc, CDK4/6, JAK2, p-STAT3/5, PIM1 and Bcl-xL, while increasing the levels of p21 and p27. Compared with OTX015, PROTAC ARV-771 treatment caused greater reduction in leukemia burden and further improved survival of NSG mice engrafted with luciferase-expressing HEL92.1.7 cells. Co-treatment with ARV-825 and JAK inhibitor ruxolitinib was synergistically lethal against established and PD CD34+ sAML cells.

ConcentrationVolumeMass	1 mg	5 mg	10 mg
1 mM	1.01 mL	5.07 mL	10.14 mL
5 mM	0.2 mL	1.01 mL	2.03 mL
10 mM	0.1 mL	0.51 mL	1.01 mL
50 mM	0.02 mL	0.1 mL	0.2 mL

Which test can confirm the anti-HSV⁃1 effect of this compound ?

The anti-HSV-1 effect of this compound in vivo was verified by plaque assay and real-time fluorescence quantitative PCR.

1/8/2016

Dear team, what is the activity of ARV-771 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.

1/12/2019

Hi, I was just wondering how ARV-771 blocks chemoradiotherapy inducible PD-L1 expression.

ARV-771 blocks chemoradiotherapy inducible PD-L1 expression by disrupting the recruitment of BRD4-IRF1 complex to PD-L1 promoter.

7/8/2020

Dear Sir, please give information about CC50 value of this compound.

The CC50 of ARV-771 against vero cells is 193.1 μmol·L-1.

28/2/2021

I want to purchase ARV-771. And how does ARV-771 suppress the cell viability and colony formation of HCC cells?

ARV-771 suppresses the cell viability and colony formation of HCC cells via arresting cell cycle progression and triggering apoptosis.

28/9/2022

I want to purchase this material. Could you tell me What the pKa value of ARV-771 is ?

The pKa value of ARV-771 is 13.61±0.46.

14/4/2023

Good antibacterial activity

In our laboratory, filter paper method was used to detect the antibacterial activity of ARV-771, and the minimum inhibitory concentration of ARV-771 against Staphylococcus aureus was 1.5 mg/mL. This indicated that it was a compound with good antibacterial activity.

16/3/2016

Inhibiting pancreatic lipase activity

The enzyme kinetics method was used by me to investigate the inhibitory effect of ARV-771 on pancreatic lipase activity. Clearly, ARV-771 significantly inhibits pancreatic lipase activity by altering its structure and microenvironment.

4/5/2016

degrade BRD2/3/4 in 22Rv1 cells

In our lab, ARV-771 potently degrades BRD2/3/4 in 22Rv1 cells with a DC50 less than 5 nM. Very useful for our study!

8/2/2017

improve efficacy in cellular models of CRPC

In my test, ARV-771 demonstrates dramatically improved efficacy in cellular models of CRPC as compared with BET inhibition. Working out great!

21/4/2020

antiproliferative effect

In my experiment, ARV-771 shows strong antiproliferative effect on 22Rv1, VCaP, and LnCaP95 cell lines. Would recommend.

9/9/2021

A broad-spectrum antibacterial activity

We used the MTT method to determine the antibacterial activity of ARV-771, and the results showed that ARV-771 has a broad-spectrum antibacterial activity.

20/12/2022

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