ARV-771 | pan-BET degrader | CAS#1949837-12-0

MedKoo Cat#: 206827 | Name: ARV-771

Description:

WARNING: This product is for research use only, not for human or veterinary use.

ARV-771 is a small-molecule pan-BET degrader. ARV-771 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.

Chemical Structure

ARV-771

CAS#1949837-12-0

Theoretical Analysis

MedKoo Cat#: 206827

Name: ARV-771

CAS#: 1949837-12-0

Chemical Formula: C49H60ClN9O7S2

Exact Mass: 985.3746

Molecular Weight: 986.64

Elemental Analysis: C, 59.65; H, 6.13; Cl, 3.59; N, 12.78; O, 11.35; S, 6.50

Price and Availability

Size	Price	Availability
1mg	USD 65.00	Ready to ship
5mg	USD 150.00	Ready to ship
10mg	USD 250.00	Ready to ship
25mg	USD 450.00	Ready to ship
50mg	USD 650.00	Ready to ship
100mg	USD 1,150.00	Ready to ship
200mg	USD 2,050.00	Ready to ship

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Related CAS #

No Data

Synonym

ARV-771; ARV 771; ARV771.

IUPAC/Chemical Name

(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

InChi Key

PQOGZKGXGLHDGS-QQRWPDCKSA-N

InChi Code

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 Code

CC1=C(C)C(C(C2=CC=C(C)C=C2)=N[C@H]3CC(NCCOCCCOCC(N[C@@H](C(C)(C)C)C(N4[C@H](C(N[C@@H](C)C5=CC=C(C6=C(C)N=CS6)C=C5)=O)C[C@@H](O)C4)=O)=O)=O)=C(S1)N7C3=NN=C7C

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot# C21R12B02

QC Data

View QC data: current batch, Lot# C21R12B02

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

ARV-771 is a potent BET degrader based on PROTAC technology 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.

In vitro activity:

ARV-771 potently degrades BRD2/3/4 in 22Rv1 cells with a DC50 < 5 nM (Fig. 1B). This study confirmed equally potent activity in the VCaP and LnCaP95 CRPC cell lines (Fig. 1B). Next, this study ensured loss of BET function with ARV-771 by measuring levels of the c-MYC protein, a downstream effector of BET proteins. Indeed, treatment with ARV-771 resulted in depletion of c-MYC with an IC50 <1 nM (Fig. 1 C and D). In the same assay, the BET inhibitors JQ-1 and OTX015 were respectively approximately 10- and 100-fold less potent than ARV-771. Reference: Proc Natl Acad Sci U S A. 2016 Jun 28; 113(26): 7124–7129. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4932933/

In vivo activity:

In xenografts of the U2932 (Fig. 7A to E) and RIVA (Fig. 7F to K) cell lines that express high levels of TCF4, this study observed that ARV771 was able to significantly reduce tumor growth. At the end of treatment, tumors were significantly smaller in ARV771-treated mice (P<0.05; Fig 7B and G) and showed reduced levels of BRD4, TCF4, IgM and MYC expression (Fig. 7C and H), which demonstrates that the molecule could reach the tumor site at a sufficient concentration to have a functional effect. There were not any signs of toxicity within these mice, and treatment with ARV-771 was associated with a significant prolongation of their survival (P<0.05). These data provide a clear functional rationale for BET inhibition in ABC-like DLBCL and show that ARV771 is effective at eliminating TCF4 and its target genes and treating ABC-like cell lines DLBCL in vitro and in vivo. Reference: Sci Transl Med. 2019 Jun 19; 11(497): eaav5599. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724184/

	Solvent	mg/mL	mM
Solubility
	DMSO	65.9	68.22
	DMF	20.0	20.70
	DMF:PBS (pH 7.2) (1:6)	0.1	0.14
	Ethanol	55.0	56.92

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 986.64 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Jain N, Hartert K, Tadros S, Fiskus W, Havranek O, Ma MCJ, Bouska A, Heavican T, Kumar D, Deng Q, Moore D, Pak C, Liu CL, Gentles AJ, Hartmann E, Kridel R, Smedby KE, Juliusson G, Rosenquist R, Gascoyne RD, Rosenwald A, Giancotti F, Neelapu SS, Westin J, Vose JM, Lunning MA, Greiner T, Rodig S, Iqbal J, Alizadeh AA, Davis RE, Bhalla K, Green MR. Targetable genetic alterations of TCF4 (E2-2) drive immunoglobulin expression in diffuse large B cell lymphoma. Sci Transl Med. 2019 Jun 19;11(497):eaav5599. doi: 10.1126/scitranslmed.aav5599. PMID: 31217338; PMCID: PMC6724184. 2. 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. 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. doi: 10.1073/pnas.1521738113. Epub 2016 Jun 6. PMID: 27274052; PMCID: PMC4932933. 3. Jain N, Hartert K, Tadros S, Fiskus W, Havranek O, Ma MCJ, Bouska A, Heavican T, Kumar D, Deng Q, Moore D, Pak C, Liu CL, Gentles AJ, Hartmann E, Kridel R, Smedby KE, Juliusson G, Rosenquist R, Gascoyne RD, Rosenwald A, Giancotti F, Neelapu SS, Westin J, Vose JM, Lunning MA, Greiner T, Rodig S, Iqbal J, Alizadeh AA, Davis RE, Bhalla K, Green MR. Targetable genetic alterations of TCF4 (E2-2) drive immunoglobulin expression in diffuse large B cell lymphoma. Sci Transl Med. 2019 Jun 19;11(497):eaav5599. doi: 10.1126/scitranslmed.aav5599. PMID: 31217338; PMCID: PMC6724184. 4. 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. BET protein proteolysis targeting chimera (PROTAC) exerts potent lethal activity against mantle cell lymphoma cells. Leukemia. 2018 Feb;32(2):343-352. doi: 10.1038/leu.2017.207. Epub 2017 Jun 30. PMID: 28663582.

In vitro protocol:

In vivo protocol:

1: Jiang YY, Jiang Y, Li CQ, Zhang Y, Dakle P, Kaur H, Deng JW, Lin RY, Han L, Xie JJ, Yan Y, Doan N, Zheng Y, Mayakonda A, Hazawa M, Xu L, Li Y, Aswad L, Jeitany M, Kanojia D, Guan XY, Said JW, Yang W, Fullwood MJ, Lin DC, Koeffler HP. TP63, SOX2, and KLF5 Establish a Core Regulatory Circuitry That Controls Epigenetic and Transcription Patterns in Esophageal Squamous Cell Carcinoma Cell Lines. Gastroenterology. 2020 Oct;159(4):1311-1327.e19. doi: 10.1053/j.gastro.2020.06.050. Epub 2020 Jun 30. PMID: 32619460. 2: Saenz DT, Fiskus W, Manshouri T, Mill CP, Qian Y, Raina K, Rajapakshe K, Coarfa C, Soldi R, Bose P, Borthakur G, Kadia TM, Khoury JD, Masarova L, Nowak AJ, Sun B, Saenz DN, Kornblau SM, Horrigan S, Sharma S, Qiu P, Crews CM, Verstovsek S, Bhalla KN. Targeting nuclear β-catenin as therapy for post- myeloproliferative neoplasm secondary AML. Leukemia. 2019 Jun;33(6):1373-1386. doi: 10.1038/s41375-018-0334-3. Epub 2018 Dec 21. PMID: 30575820. 3: 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. BET protein proteolysis targeting chimera (PROTAC) exerts potent lethal activity against mantle cell lymphoma cells. Leukemia. 2018 Feb;32(2):343-352. doi: 10.1038/leu.2017.207. Epub 2017 Jun 30. PMID: 28663582. 4: 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. Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells. Leukemia. 2017 Sep;31(9):1951-1961. doi: 10.1038/leu.2016.393. Epub 2017 Feb 2. PMID: 28042144; PMCID: PMC5537055. 5: 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. 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. doi: 10.1073/pnas.1521738113. Epub 2016 Jun 6. PMID: 27274052; PMCID: PMC4932933.