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MedKoo Cat#: 407405 | Name: ARV-825
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Description:

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

ARV-825 is a PROTAC (proteolysis-targeting chimera). ARV-825 exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells. Co-treatment with ARV-825 and JAK inhibitor ruxolitinib was synergistically lethal against established and PD CD34+ sAML cells. Notably, ARV-825 induced high levels of apoptosis in the in vitro generated ruxolitinib-persister or ruxolitinib-resistant sAML cells. These findings strongly support the in vivo testing of the BRD4-PROTAC based combinations against post-MPN sAML.

Chemical Structure

ARV-825
ARV-825
CAS#1818885-28-7

Theoretical Analysis

MedKoo Cat#: 407405

Name: ARV-825

CAS#: 1818885-28-7

Chemical Formula: C46H47ClN8O9S

Exact Mass: 922.2875

Molecular Weight: 923.44

Elemental Analysis: C, 59.83; H, 5.13; Cl, 3.84; N, 12.13; O, 15.59; S, 3.47

Price and Availability

Size Price Availability Quantity
5mg USD 150.00 Ready to ship
10mg USD 250.00 Ready to ship
25mg USD 550.00 Ready to ship
50mg USD 950.00 Ready to ship
100mg USD 1,650.00 Ready to ship
200mg USD 2,950.00 Ready to ship
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Related CAS #
No Data
Synonym
ARV-825; ARV 825; ARV825.
IUPAC/Chemical Name
2-((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)-N-(4-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)acetamide
InChi Key
RWLOGRLTDKDANT-TYIYNAFKSA-N
InChi Code
InChI=1S/C46H47ClN8O9S/c1-26-27(2)65-46-39(26)41(29-7-9-30(47)10-8-29)50-35(42-53-52-28(3)54(42)46)25-38(57)49-31-11-13-32(14-12-31)64-24-23-63-22-21-62-20-19-61-18-17-48-34-6-4-5-33-40(34)45(60)55(44(33)59)36-15-16-37(56)51-43(36)58/h4-14,35-36,48H,15-25H2,1-3H3,(H,49,57)(H,51,56,58)/t35-,36?/m0/s1
SMILES Code
O=C(NC1=CC=C(OCCOCCOCCOCCNC2=CC=CC(C(N3C(CC4)C(NC4=O)=O)=O)=C2C3=O)C=C1)C[C@H]5C6=NN=C(C)N6C7=C(C(C)=C(C)S7)C(C8=CC=C(Cl)C=C8)=N5
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
Biological target:
ARV-825 is a BRD4 degrader based on PROTAC technology that binds to BD1 and BD2 of BRD4 with Kds of 90 and 28 nM, respectively.
In vitro activity:
BL cells are known to be sensitive to BRD4 inhibitors, which suppress c-MYC signaling and inhibit cell proliferation. Because ARV-825 treatment results in prolonged BRD4 down-regulation and downstream signaling suppression compared to BRD4 inhibitors, it was hypothesized that it would provide superior functional effects compared to the inhibitors. Indeed, ARV-825 leads to more pronounced suppression of proliferation than both JQ1 and OTX015 in all BL cell lines tested (Figure 4A). Moreover, the proliferation suppression effect of ARV-825 is sustained longer than that of JQ1 and OTX015 after the removal of compounds following a 24-hr treatment (Figure 4B). This is consistent with our earlier findings that ARV-825 provides long-lasting effect on BRD4 degradation and downstream signaling repression (Figure 3B and 3C). As demonstrated in Figure 2C, presence of excess cereblon ligand, pomalidomide, is able to prevent efficient BRD4 degradation induced by ARV-825 due to competition of cereblon binding. Consistently, the presence of excessive pomalidomide rescued the proliferation suppression effect of ARV-825 in BL cells in a dose-dependent manner (Figure 4C). Importantly, pomalidomide alone didn’t show any significant effects on the proliferation of these cell lines (Figure 4D). Reference: Chem Biol. 2015 Jun 18;22(6):755-63. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/26051217/
In vivo activity:
To further investigate the in vivo activity of ARV-825, a pre-clinical model of neuroblastoma using the MYCN-amplified SK-N-BE(2) cell was developed. Five mg/kg ARV-825 was administrated daily when the subcutaneous tumor reached a size of 100 mm3. A significant reduction in tumor burden was observed in mice with ARV-825 treatment group compared to those in the control group (Figure 8A). The xenograft tumor weight was reduced in mice receiving ARV-825 treatment, but no significant difference in mice body weight was observed between the treatment and control group (Figures 8B–D). The proportion of Ki67 positive cells was much lesser in tumors from ARV-825-treated mice (Figures 8E, F), indicating a reduction in proliferative activity. Besides that, ARV-825 treatment downregulated the BRD4 and MYCN protein expression in ARV-825-treated xenograft tumors than in the control group (Figures 8G, H), which is consistent with the in vitro results. These observations suggest that ARV-825 can effectively suppress tumor growth in the subcutaneous NB xenograft model. Reference: Front Oncol. 2020 Nov 26;10:574525. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/33324552/
Solvent mg/mL mM
Solubility
DMSO 5.0 5.41
DMF 5.0 5.41
Water 0.0 0.00
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 923.44 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.

Recalculate based on batch purity %
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:
In vitro protocol:
1. Lu J, Qian Y, Altieri M, Dong H, Wang J, Raina K, Hines J, Winkler JD, Crew AP, Coleman K, Crews CM. Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4. Chem Biol. 2015 Jun 18;22(6):755-63. doi: 10.1016/j.chembiol.2015.05.009. Epub 2015 Jun 4. PMID: 26051217; PMCID: PMC4475452. 2. Li Z, Lim SL, Tao Y, Li X, Xie Y, Yang C, Zhang Z, Jiang Y, Zhang X, Cao X, Wang H, Qian G, Wu Y, Li M, Fang F, Liu Y, Fu M, Ding X, Zhu Z, Lv H, Lu J, Xiao S, Hu S, Pan J. PROTAC Bromodomain Inhibitor ARV-825 Displays Anti-Tumor Activity in Neuroblastoma by Repressing Expression of MYCN or c-Myc. Front Oncol. 2020 Nov 26;10:574525. doi: 10.3389/fonc.2020.574525. PMID: 33324552; PMCID: PMC7726414.
In vivo protocol:
1. Li Z, Lim SL, Tao Y, Li X, Xie Y, Yang C, Zhang Z, Jiang Y, Zhang X, Cao X, Wang H, Qian G, Wu Y, Li M, Fang F, Liu Y, Fu M, Ding X, Zhu Z, Lv H, Lu J, Xiao S, Hu S, Pan J. PROTAC Bromodomain Inhibitor ARV-825 Displays Anti-Tumor Activity in Neuroblastoma by Repressing Expression of MYCN or c-Myc. Front Oncol. 2020 Nov 26;10:574525. doi: 10.3389/fonc.2020.574525. PMID: 33324552; PMCID: PMC7726414.
1: Zhao Y, Niu Q, Yang S, Yang J, Zhang Z, Geng S, Fan J, Liu Z, Guan G, Liu Z, Zhou J, Hu H, Luo J, Yin H. Inhibition of BET Family Proteins Suppresses African Swine Fever Virus Infection. Microbiol Spectr. 2022 Jun 27:e0241921. doi: 10.1128/spectrum.02419-21. Epub ahead of print. PMID: 35758684. 2: Yang T, Hu Y, Miao J, Chen J, Liu J, Cheng Y, Gao X. A BRD4 PROTAC nanodrug for glioma therapy via the intervention of tumor cells proliferation, apoptosis and M2 macrophages polarization. Acta Pharm Sin B. 2022 Jun;12(6):2658-2671. doi: 10.1016/j.apsb.2022.02.009. Epub 2022 Feb 16. PMID: 35755286; PMCID: PMC9214068. 3: Zhang S, Bai P, Lei D, Liang Y, Zhen S, Bakiasi G, Pang H, Choi SH, Wang C, Tanzi RE, Zhang C. Degradation and inhibition of epigenetic regulatory protein BRD4 exacerbate Alzheimer's disease-related neuropathology in cell models. J Biol Chem. 2022 Apr;298(4):101794. doi: 10.1016/j.jbc.2022.101794. Epub 2022 Mar 3. PMID: 35248531; PMCID: PMC8958546. 4: Piya S, Yang Y, Bhattacharya S, Sharma P, Ma H, Mu H, He H, Ruvolo V, Baran N, Davis RE, Jain AK, Konopleava M, Kantarjian H, Andreeff M, You MJ, Borthakur G. Targeting the NOTCH1-MYC-CD44 axis in leukemia-initiating cells in T-ALL. Leukemia. 2022 May;36(5):1261-1273. doi: 10.1038/s41375-022-01516-1. Epub 2022 Feb 16. PMID: 35173274; PMCID: PMC9061299. 5: Vartak R, Saraswat A, Yang Y, Chen ZS, Patel K. Susceptibility of Lung Carcinoma Cells to Nanostructured Lipid Carrier of ARV-825, a BRD4 Degrading Proteolysis Targeting Chimera. Pharm Res. 2022 Feb 10. doi: 10.1007/s11095-022-03184-3. Epub ahead of print. PMID: 35146591. 6: Saraswat A, Vemana HP, Dukhande VV, Patel K. Galactose-decorated liver tumor- specific nanoliposomes incorporating selective BRD4-targeted PROTAC for hepatocellular carcinoma therapy. Heliyon. 2022 Jan 3;8(1):e08702. doi: 10.1016/j.heliyon.2021.e08702. PMID: 35036599; PMCID: PMC8749201. 7: Liao X, Qian X, Zhang Z, Tao Y, Li Z, Zhang Q, Liang H, Li X, Xie Y, Zhuo R, Chen Y, Jiang Y, Cao H, Niu J, Xue C, Ni J, Pan J, Cui D. ARV-825 Demonstrates Antitumor Activity in Gastric Cancer via MYC-Targets and G2M-Checkpoint Signaling Pathways. Front Oncol. 2021 Oct 18;11:753119. doi: 10.3389/fonc.2021.753119. PMID: 34733788; PMCID: PMC8559897. 8: O'Connell N. Protein Ligand Interactions Using Surface Plasmon Resonance. Methods Mol Biol. 2021;2365:3-20. doi: 10.1007/978-1-0716-1665-9_1. PMID: 34432236. 9: Fu Y, Saraswat A, Wei Z, Agrawal MY, Dukhande VV, Reznik SE, Patel K. Development of Dual ARV-825 and Nintedanib-Loaded PEGylated Nano-Liposomes for Synergistic Efficacy in Vemurafnib-Resistant Melanoma. Pharmaceutics. 2021 Jul 1;13(7):1005. doi: 10.3390/pharmaceutics13071005. PMID: 34371697; PMCID: PMC8308940. 10: Wu S, Jiang Y, Hong Y, Chu X, Zhang Z, Tao Y, Fan Z, Bai Z, Li X, Chen Y, Li Z, Ding X, Lv H, Du X, Lim SL, Zhang Y, Huang S, Lu J, Pan J, Hu S. BRD4 PROTAC degrader ARV-825 inhibits T-cell acute lymphoblastic leukemia by targeting 'Undruggable' Myc-pathway genes. Cancer Cell Int. 2021 Apr 22;21(1):230. doi: 10.1186/s12935-021-01908-w. PMID: 33888130; PMCID: PMC8061034. 11: Li Z, Lim SL, Tao Y, Li X, Xie Y, Yang C, Zhang Z, Jiang Y, Zhang X, Cao X, Wang H, Qian G, Wu Y, Li M, Fang F, Liu Y, Fu M, Ding X, Zhu Z, Lv H, Lu J, Xiao S, Hu S, Pan J. PROTAC Bromodomain Inhibitor ARV-825 Displays Anti-Tumor Activity in Neuroblastoma by Repressing Expression of MYCN or c-Myc. Front Oncol. 2020 Nov 26;10:574525. doi: 10.3389/fonc.2020.574525. PMID: 33324552; PMCID: PMC7726414. 12: Minko T. Nanoformulation of BRD4-Degrading PROTAC: Improving Druggability To Target the 'Undruggable' MYC in Pancreatic Cancer. Trends Pharmacol Sci. 2020 Oct;41(10):684-686. doi: 10.1016/j.tips.2020.08.008. Epub 2020 Sep 4. PMID: 32893006. 13: Saraswat A, Patki M, Fu Y, Barot S, Dukhande VV, Patel K. Nanoformulation of PROteolysis TArgeting Chimera targeting 'undruggable' c-Myc for the treatment of pancreatic cancer. Nanomedicine (Lond). 2020 Aug;15(18):1761-1777. doi: 10.2217/nnm-2020-0156. Epub 2020 Jul 23. PMID: 32698663. 14: Lim SL, Xu L, Han BC, Shyamsunder P, Chng WJ, Koeffler HP. Multiple myeloma: Combination therapy of BET proteolysis targeting chimeric molecule with CDK9 inhibitor. PLoS One. 2020 Jun 19;15(6):e0232068. doi: 10.1371/journal.pone.0232068. PMID: 32559187; PMCID: PMC7304913. 15: Lee SM, Kang CH, Choi SU, Kim Y, Hwang JY, Jeong HG, Park CH. A Chemical Switch System to Modulate Chimeric Antigen Receptor T Cell Activity through Proteolysis-Targeting Chimaera Technology. ACS Synth Biol. 2020 May 15;9(5):987-992. doi: 10.1021/acssynbio.9b00476. Epub 2020 Apr 30. PMID: 32352759. 16: Zhang MY, Liu SL, Huang WL, Tang DB, Zheng WW, Zhou N, Zhou H, Abudureheman T, Tang ZH, Zhou BS, Duan CW. Bromodomains and Extra-Terminal (BET) Inhibitor JQ1 Suppresses Proliferation of Acute Lymphocytic Leukemia by Inhibiting c-Myc- Mediated Glycolysis. Med Sci Monit. 2020 Apr 8;26:e923411. doi: 10.12659/MSM.923411. PMID: 32266878; PMCID: PMC7165247. 17: He L, Chen C, Gao G, Xu K, Ma Z. ARV-825-induced BRD4 protein degradation as a therapy for thyroid carcinoma. Aging (Albany NY). 2020 Mar 12;12(5):4547-4557. doi: 10.18632/aging.102910. Epub 2020 Mar 12. PMID: 32163373; PMCID: PMC7093165. 18: Lu Q, Ding X, Huang T, Zhang S, Li Y, Xu L, Chen G, Ying Y, Wang Y, Feng Z, Wang L, Zou X. BRD4 degrader ARV-825 produces long-lasting loss of BRD4 protein and exhibits potent efficacy against cholangiocarcinoma cells. Am J Transl Res. 2019 Sep 15;11(9):5728-5739. PMID: 31632543; PMCID: PMC6789278. 19: Noblejas-López MDM, Nieto-Jimenez C, Burgos M, Gómez-Juárez M, Montero JC, Esparís-Ogando A, Pandiella A, Galán-Moya EM, Ocaña A. Activity of BET- proteolysis targeting chimeric (PROTAC) compounds in triple negative breast cancer. J Exp Clin Cancer Res. 2019 Aug 30;38(1):383. doi: 10.1186/s13046-019-1387-5. PMID: 31470872; PMCID: PMC6717344. 20: Rathod D, Fu Y, Patel K. BRD4 PROTAC as a novel therapeutic approach for the treatment of vemurafenib resistant melanoma: Preformulation studies, formulation development and in vitro evaluation. Eur J Pharm Sci. 2019 Oct 1;138:105039. doi: 10.1016/j.ejps.2019.105039. Epub 2019 Aug 5. PMID: 31394259. 21: Chen Y, Xu L, Mayakonda A, Huang ML, Kanojia D, Tan TZ, Dakle P, Lin RY, Ke XY, Said JW, Chen J, Gery S, Ding LW, Jiang YY, Pang A, Puhaindran ME, Goh BC, Koeffler HP. Bromodomain and extraterminal proteins foster the core transcriptional regulatory programs and confer vulnerability in liposarcoma. Nat Commun. 2019 Mar 22;10(1):1353. doi: 10.1038/s41467-019-09257-z. PMID: 30903020; PMCID: PMC6430783. 22: Piya S, Mu H, Bhattacharya S, Lorenzi PL, Davis RE, McQueen T, Ruvolo V, Baran N, Wang Z, Qian Y, Crews CM, Konopleva M, Ishizawa J, You MJ, Kantarjian H, Andreeff M, Borthakur G. BETP degradation simultaneously targets acute myelogenous leukemia stem cells and the microenvironment. J Clin Invest. 2019 Feb 21;129(5):1878-1894. doi: 10.1172/JCI120654. PMID: 30829648; PMCID: PMC6486356. 23: Lim SL, Damnernsawad A, Shyamsunder P, Chng WJ, Han BC, Xu L, Pan J, Pravin DP, Alkan S, Tyner JW, Koeffler HP. Proteolysis targeting chimeric molecules as therapy for multiple myeloma: efficacy, biomarker and drug combinations. Haematologica. 2019 Jun;104(6):1209-1220. doi: 10.3324/haematol.2018.201483. Epub 2019 Jan 3. PMID: 30606790; PMCID: PMC6545861. 24: Sahni JM, Keri RA. Targeting bromodomain and extraterminal proteins in breast cancer. Pharmacol Res. 2018 Mar;129:156-176. doi: 10.1016/j.phrs.2017.11.015. Epub 2017 Nov 16. PMID: 29154989; PMCID: PMC5828951. 25: Tarantelli C, Gaudio E, Arribas AJ, Kwee I, Hillmann P, Rinaldi A, Cascione L, Spriano F, Bernasconi E, Guidetti F, Carrassa L, Pittau RB, Beaufils F, Ritschard R, Rageot D, Sele A, Dossena B, Rossi FM, Zucchetto A, Taborelli M, Gattei V, Rossi D, Stathis A, Stussi G, Broggini M, Wymann MP, Wicki A, Zucca E, Cmiljanovic V, Fabbro D, Bertoni F. PQR309 Is a Novel Dual PI3K/mTOR Inhibitor with Preclinical Antitumor Activity in Lymphomas as a Single Agent and in Combination Therapy. Clin Cancer Res. 2018 Jan 1;24(1):120-129. doi: 10.1158/1078-0432.CCR-17-1041. Epub 2017 Oct 24. PMID: 29066507. 26: 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. 27: 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. 28: Abruzzese MP, Bilotta MT, Fionda C, Zingoni A, Soriani A, Vulpis E, Borrelli C, Zitti B, Petrucci MT, Ricciardi MR, Molfetta R, Paolini R, Santoni A, Cippitelli M. Inhibition of bromodomain and extra-terminal (BET) proteins increases NKG2D ligand MICA expression and sensitivity to NK cell-mediated cytotoxicity in multiple myeloma cells: role of cMYC-IRF4-miR-125b interplay. J Hematol Oncol. 2016 Dec 1;9(1):134. doi: 10.1186/s13045-016-0362-2. PMID: 27903272; PMCID: PMC5131470. 29: Lu J, Qian Y, Altieri M, Dong H, Wang J, Raina K, Hines J, Winkler JD, Crew AP, Coleman K, Crews CM. Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4. Chem Biol. 2015 Jun 18;22(6):755-63. doi: 10.1016/j.chembiol.2015.05.009. Epub 2015 Jun 4. PMID: 26051217; PMCID: PMC4475452.