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Purity: =99.29%
ARV-771 (ARV771) is a novel and potent PROTAC-based degrader of bromodomain and extra-terminal (BET) proteins with the potential to be used in the treatment of cancers such as CRPC. It induces the degradation of BET proteins in castrate-resistent prostate cancer (CRPC) cultures (BRD2/3/4 DC50<5 nM; 22Rv1, VCaP & LnCaP95) and reduces downstream c-Myc transcription with 10-500-fold higher potency than JQ-1, OTX015, and dBET1. ARV-771 also inhibits BRD with Kd values of 4.7, 7.6, 7.6 nM against BRD2, BRD3 and BRD4, respectively. 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. 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 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.
| Targets |
BRD2 (Kd = 4.7~34 nM); BRD3 (Kd = 8.3 nM); BRD4 (Kd = 9.6 nM)
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| ln Vitro |
In comparison to BET inhibition, ARV-771, a small-molecule pan-BET degrader based on proteolysis-targeting chimera (PROTAC) technology, shows markedly increased efficacy in CRPC cellular models. With a DC50 of less than 5 nM, ARV-771 potently destroys BRD2/3/4 in 22Rv1 cells. One of BET proteins' downstream effectors is the c-MYC protein. When c-MYC is treated with ARV-771, its levels are reduced with an IC50 of less than 1 nM. ARV-771 demonstrates a potent antiproliferative effect on cell lines that are 22Rv1, VCaP, and LnCaP95. Treatment with ARV-771 significantly alters cell shape in a way that is consistent with apoptosis. Treatment with 10 nM ARV-771 causes a down-regulation of FL-AR and AR-V7 mRNA in VCaP cells. In VCaP cells, ARV-771 exhibits antiandrogenic activity on several AR-regulated genes[1].
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| ln Vivo |
When non-castrated male Nu/Nu mice with tumor xenografts carrying AR-V7+ 22Rv1 are given daily subcutaneous injections of ARV-771 at a dose of 10 mg/kg for three days, the levels of BRD4 and c-MYC in the tumor tissue are down-regulated by 37% and 76%, respectively. Following ARV-771 treatment, a notable down-regulation in AR-V7 levels is seen in the 22Rv1 tumors[1].
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| Enzyme Assay |
c-MYC ELISA. [1]
22Rv1 cells (30,000 cells per well) were dosed with compounds serially diluted at 1:3 ratio for an eight-point dose curve. The medium was aspirated, and cells were washed once with PBS. RIPA buffer (50 μL) supplemented with protease and phosphatase inhibitors was used to lyse cells. Lysates were centrifuged and transferred to a 96-well c-MYC ELISA plate. AR ELISA. [1] VCaP cells (40,000 cells per well) were dosed with compounds serially diluted at 1:3 ratio for an eight-point dose curve. Medium was aspirated, and cells were lysed in cell lysis buffer supplemented with protease and phosphatase inhibitors. Lysates were centrifuged and transferred to a 96-well Androgen Receptor ELISA plate |
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| Cell Assay |
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| Animal Protocol |
Mice were implanted subcutaneously with 5 × 106 22Rv1 or VCaP cells in Matrigel. Dosing was carried out for up to 3 wk, depending on the experiment. Mice were sacrificed 8 h after the final dose. Plasma and tissues were harvested and flash frozen for further analysis. All PK analysis was carried out at Drumetix Laboratories. Plasma PSA was analyzed by the PathScan Total PSA/KLK3 Sandwich ELISA Kit following the manufacturer’s protocol.[1]
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| References | ||
| Additional Infomation |
In this study, we demonstrate that 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 the decrease of both FL-AR and AR-V7 at the transcript level. In contrast, treatment of 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. Finally, subcutaneous delivery of ARV-771 is efficacious in two different mouse models of CRPC and results in tumor regression in enzalutamide-resistant 22Rv1 xenografts. Thus, this study validates BET protein degradation as a promising clinical strategy against metastatic CRPC and demonstrates the feasibility of treating solid-tumor malignancies with small-molecule–mediated protein degradation using PROTACs.[1]
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| Molecular Formula |
C49H60CLN9O7S2
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|---|---|
| Molecular Weight |
986.6398
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| Exact Mass |
985.374
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| Elemental Analysis |
C, 59.65; H, 6.13; Cl, 3.59; N, 12.78; O, 11.35; S, 6.50
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| CAS # |
1949837-12-0
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| PubChem CID |
126619980
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| Appearance |
Typically exists as White to light yellow solids at room temperature
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.674
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| LogP |
3.84
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
13
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| Rotatable Bond Count |
19
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| Heavy Atom Count |
68
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| Complexity |
1750
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| Defined Atom Stereocenter Count |
5
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| SMILES |
ClC1C([H])=C([H])C(=C([H])C=1[H])C1C2C(C([H])([H])[H])=C(C([H])([H])[H])SC=2N2C(C([H])([H])[H])=NN=C2[C@]([H])(C([H])([H])C(N([H])C([H])([H])C([H])([H])OC([H])([H])C([H])([H])C([H])([H])OC([H])([H])C(N([H])[C@]([H])(C(N2C([H])([H])[C@@]([H])(C([H])([H])[C@@]2([H])C(N([H])[C@@]([H])(C([H])([H])[H])C2C([H])=C([H])C(C3=C(C([H])([H])[H])N=C([H])S3)=C([H])C=2[H])=O)O[H])=O)C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])=O)=O)N=1
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| InChi Key |
HJGNHEQIOZDQRW-VZRXUJQISA-N
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| InChi Code |
InChI=1S/C50H63N9O7S2/c1-28-11-13-35(14-12-28)43-42-29(2)32(5)68-49(42)59-33(6)56-57-46(59)38(54-43)24-40(61)51-19-22-65-20-10-21-66-26-41(62)55-45(50(7,8)9)48(64)58-25-37(60)23-39(58)47(63)53-30(3)34-15-17-36(18-16-34)44-31(4)52-27-67-44/h11-18,27,30,37-39,45,60H,10,19-26H2,1-9H3,(H,51,61)(H,53,63)(H,55,62)/t30-,37+,38-,39-,45+/m0/s1
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| Chemical Name |
(2S,4R)-1-((S)-2-(tert-butyl)-4,14-dioxo-15-((S)-2,3,9-trimethyl-4-(p-tolyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-6,10-dioxa-3,13-diazapentadecanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
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| Synonyms |
ARV771; ARV 771; CHEMBL4215078; (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; (2S,4R)-1-((2S)-2-(tert-butyl)-15-((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)-4,14-dioxo-6,10-dioxa-3,13-diazapentadecan-1-oyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (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; ARV771; SCHEMBL18551355; ARV-771.
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ≥ 50 mg/mL (~50.68 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (2.53 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (2.53 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (2.53 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.0135 mL | 5.0677 mL | 10.1354 mL | |
| 5 mM | 0.2027 mL | 1.0135 mL | 2.0271 mL | |
| 10 mM | 0.1014 mL | 0.5068 mL | 1.0135 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
 BRD4 PROTAC schematic.
ARV-771 treatment attenuates AR signaling.Proc Natl Acad Sci U S A.2016 Jun 28;113(26):7124-9. |
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 ARV-771 is a potent pan-BET degrader.Proc Natl Acad Sci U S A.2016 Jun 28;113(26):7124-9. |
 ARV-771 treatment results in cell death in CRPC cell lines.
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