WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 206324
CAS#: 1431280-51-1
Description: VLX1570 is an inhibitor of the 19S proteasome-specific deubiquitylating enzymes (DUBs) USP14 and UCHL5, with apoptosis-inducing and antineoplastic activities. Upon administration, VLX1570 specifically binds to both USP14 and UCHL5, thereby blocking their deubiquitylating activity. This blocks the ubiquitin proteasome degradation pathway, prevents the degradation of defective proteins, and leads to an accumulation of poly-ubiquitylated proteins. This induces the unfolded protein response (UPR) and results in both the induction of tumor cell apoptosis and the inhibition of tumor cell growth.
MedKoo Cat#: 206324
Name: VLX1570
CAS#: 1431280-51-1
Chemical Formula: C23H17F2N3O6
Exact Mass: 469.1085
Molecular Weight: 469.4008
Elemental Analysis: C, 58.85; H, 3.65; F, 8.09; N, 8.95; O, 20.45
Synonym: VLX-1570, VLX1570, VLX 1570
IUPAC/Chemical Name: 1-acryloyl-3,5-bis((Z)-4-fluoro-3-nitrobenzylidene)azepan-4-one
InChi Key: SCKXBVLYWLLALY-CQRYCMKKSA-N
InChi Code: InChI=1S/C23H17F2N3O6/c1-2-22(29)26-8-7-16(9-14-3-5-18(24)20(11-14)27(31)32)23(30)17(13-26)10-15-4-6-19(25)21(12-15)28(33)34/h2-6,9-12H,1,7-8,13H2/b16-9-,17-10-
SMILES Code: O=C1/C(CN(C(C=C)=O)CC/C1=C/C2=CC=C(F)C([N+]([O-])=O)=C2)=C\C3=CC=C(F)C([N+]([O-])=O)=C3
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, not in water
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
| Biological target: | VLX1570 is a competitive inhibitor of proteasome deubiquitinases (DUBs) with an IC50 of approximate 10 μM. |
| In vitro activity: | Inhibition of proteasome ubiquitin processing following VLX1570 treatment results in the accumulation of high molecular weight polyubiquitinated substrates in cells. A dose-dependent increase in high-molecular polyubiquitinated proteins in ALL cells following exposure to VLX1570 (Figure 1B) was found. The increases in polyubiquitinated proteins occurred at drug concentrations that reduced the number of viable cells (50 – 100 nM), consistent with the notion that the growth inhibitory effect of the drug is due to UPS inhibition. The extent of accumulation of misfolded protein substrates in VLX1570-exposed cells was previously found to be associated with cytotoxicity. In general cells with high protein turnover rates respond to decreased UPS flux via the induction of chaperones to counteract the accumulation of misfolded proteins. VLX1570 increased the expression of the inducible form of Hsp70 (HSP70B´) in all ALL cell lines tested (Figure 1B). Induction of HSP70B´ was generally observed at drug concentrations that induced the accumulation of polyubiquitin. Reference: Oncotarget. 2017 Mar 28; 8(13): 21115–21127. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5400570/ |
| In vivo activity: | To evaluate the in vivo activity of benzyl-4-piperidone compounds, a GFP-luciferase expressing A673 xenograft model was treated with b-AP15 following injection of cells to study the effect on tumor formation. Treatment with b-AP15 resulted in undetectable tumors by imaging at 4 weeks (Fig S3A). Next, bortezomib and b-AP15 were compared in an A673 xenograft model and demonstrated superior growth inhibition and improved survival with the former (Fig S3B and S3C). The ability of b-AP15 and VLX1570 to inhibit the growth of two EWS cell line xenografts, A673 and TC-71, was tested. Athymic mice were treated with bAP15 (25mg/kg), VLX1570 (4.4mg/kg), or vehicle daily via intraperitoneal administration. Growth of A673 and TC-71 xenograft tumors was significantly reduced by both compounds with VLX1570 being more potent (Fig. 3C). Reference: Cancer Res. 2016 Aug 1; 76(15): 4525–4534. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5484002/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMF | 25.0 | 53.26 | |
| DMF:PBS (pH 7.2) (1:2) | 0.3 | 0.64 | |
| DMSO | 47.0 | 100.13 |
The following data is based on the product molecular weight 469.4008 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. Pellegrini P, Selvaraju K, Faustini E, Mofers A, Zhang X, Ternerot J, Schubert A, Linder S, D Arcy P. Induction of ER Stress in Acute Lymphoblastic Leukemia Cells by the Deubiquitinase Inhibitor VLX1570. Int J Mol Sci. 2020 Jul 4;21(13):4757. doi: 10.3390/ijms21134757. PMID: 32635430; PMCID: PMC7369842. 2. Mazurkiewicz M, Hillert EK, Wang X, Pellegrini P, Olofsson MH, Selvaraju K, D'Arcy P, Linder S. Acute lymphoblastic leukemia cells are sensitive to disturbances in protein homeostasis induced by proteasome deubiquitinase inhibition. Oncotarget. 2017 Mar 28;8(13):21115-21127. doi: 10.18632/oncotarget.15501. PMID: 28423502; PMCID: PMC5400570. 3. Shukla N, Somwar R, Smith RS, Ambati S, Munoz S, Merchant M, D'Arcy P, Wang X, Kobos R, Antczak C, Bhinder B, Shum D, Radu C, Yang G, Taylor BS, Ng CK, Weigelt B, Khodos I, de Stanchina E, Reis-Filho JS, Ouerfelli O, Linder S, Djaballah H, Ladanyi M. Proteasome Addiction Defined in Ewing Sarcoma Is Effectively Targeted by a Novel Class of 19S Proteasome Inhibitors. Cancer Res. 2016 Aug 1;76(15):4525-34. doi: 10.1158/0008-5472.CAN-16-1040. Epub 2016 Jun 2. PMID: 27256563; PMCID: PMC5484002. |
| In vitro protocol: | 1. Pellegrini P, Selvaraju K, Faustini E, Mofers A, Zhang X, Ternerot J, Schubert A, Linder S, D Arcy P. Induction of ER Stress in Acute Lymphoblastic Leukemia Cells by the Deubiquitinase Inhibitor VLX1570. Int J Mol Sci. 2020 Jul 4;21(13):4757. doi: 10.3390/ijms21134757. PMID: 32635430; PMCID: PMC7369842. 2. Mazurkiewicz M, Hillert EK, Wang X, Pellegrini P, Olofsson MH, Selvaraju K, D'Arcy P, Linder S. Acute lymphoblastic leukemia cells are sensitive to disturbances in protein homeostasis induced by proteasome deubiquitinase inhibition. Oncotarget. 2017 Mar 28;8(13):21115-21127. doi: 10.18632/oncotarget.15501. PMID: 28423502; PMCID: PMC5400570. |
| In vivo protocol: | 1. Shukla N, Somwar R, Smith RS, Ambati S, Munoz S, Merchant M, D'Arcy P, Wang X, Kobos R, Antczak C, Bhinder B, Shum D, Radu C, Yang G, Taylor BS, Ng CK, Weigelt B, Khodos I, de Stanchina E, Reis-Filho JS, Ouerfelli O, Linder S, Djaballah H, Ladanyi M. Proteasome Addiction Defined in Ewing Sarcoma Is Effectively Targeted by a Novel Class of 19S Proteasome Inhibitors. Cancer Res. 2016 Aug 1;76(15):4525-34. doi: 10.1158/0008-5472.CAN-16-1040. Epub 2016 Jun 2. PMID: 27256563; PMCID: PMC5484002. |
1: Mazurkiewicz M, Hillert EK, Wang X, Pellegrini P, Olofsson MH, Selvaraju K, D'Arcy P, Linder S. Acute lymphoblastic leukemia cells are sensitive to disturbances in protein homeostasis induced by proteasome deubiquitinase inhibition. Oncotarget. 2017 Mar 28;8(13):21115-21127. doi: 10.18632/oncotarget.15501. PubMed PMID: 28423502; PubMed Central PMCID: PMC5400570.
2: Paulus A, Akhtar S, Caulfield TR, Samuel K, Yousaf H, Bashir Y, Paulus SM, Tran D, Hudec R, Cogen D, Jiang J, Edenfield B, Novak A, Ansell SM, Witzig T, Martin P, Coleman M, Roy V, Ailawadhi S, Chitta K, Linder S, Chanan-Khan A. Coinhibition of the deubiquitinating enzymes, USP14 and UCHL5, with VLX1570 is lethal to ibrutinib- or bortezomib-resistant Waldenstrom macroglobulinemia tumor cells. Blood Cancer J. 2016 Nov 4;6(11):e492. doi: 10.1038/bcj.2016.93. PubMed PMID: 27813535; PubMed Central PMCID: PMC5148058.
3: Wang X, Mazurkiewicz M, Hillert EK, Olofsson MH, Pierrou S, Hillertz P, Gullbo J, Selvaraju K, Paulus A, Akhtar S, Bossler F, Khan AC, Linder S, D'Arcy P. Corrigendum: The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells. Sci Rep. 2016 Jul 29;6:30667. doi: 10.1038/srep30667. PubMed PMID: 27472448; PubMed Central PMCID: PMC4966493.
4: Wang X, Mazurkiewicz M, Hillert EK, Olofsson MH, Pierrou S, Hillertz P, Gullbo J, Selvaraju K, Paulus A, Akhtar S, Bossler F, Khan AC, Linder S, D'Arcy P. The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells. Sci Rep. 2016 Jun 6;6:26979. doi: 10.1038/srep26979. Erratum in: Sci Rep. 2016 Jul 29;6:30667. PubMed PMID: 27264969; PubMed Central PMCID: PMC4893612.
5: Shukla N, Somwar R, Smith RS, Ambati S, Munoz S, Merchant M, D'Arcy P, Wang X, Kobos R, Antczak C, Bhinder B, Shum D, Radu C, Yang G, Taylor BS, Ng CK, Weigelt B, Khodos I, de Stanchina E, Reis-Filho JS, Ouerfelli O, Linder S, Djaballah H, Ladanyi M. Proteasome Addiction Defined in Ewing Sarcoma Is Effectively Targeted by a Novel Class of 19S Proteasome Inhibitors. Cancer Res. 2016 Aug 1;76(15):4525-34. doi: 10.1158/0008-5472.CAN-16-1040. Epub 2016 Jun 2. PubMed PMID: 27256563; PubMed Central PMCID: PMC5484002.
6: Vogel RI, Pulver T, Heilmann W, Mooneyham A, Mullany S, Zhao X, Shahi M, Richter J, Klein M, Chen L, Ding R, Konecny G, Kommoss S, Winterhoff B, Ghebre R, Bazzaro M. USP14 is a predictor of recurrence in endometrial cancer and a molecular target for endometrial cancer treatment. Oncotarget. 2016 May 24;7(21):30962-76. doi: 10.18632/oncotarget.8821. PubMed PMID: 27121063; PubMed Central PMCID: PMC5058731.
7: Wang X, D'Arcy P, Caulfield TR, Paulus A, Chitta K, Mohanty C, Gullbo J, Chanan-Khan A, Linder S. Synthesis and evaluation of derivatives of the proteasome deubiquitinase inhibitor b-AP15. Chem Biol Drug Des. 2015 Nov;86(5):1036-48. doi: 10.1111/cbdd.12571. Epub 2015 May 27. PubMed PMID: 25854145; PubMed Central PMCID: PMC4846425.
Note: MedKoo has licensed VLX1570 patent from Vivolux, AB. MedKoo obtained a non-exclusive license for commercial sales of the VLX1570 substance for non-clinical research use. VLX1570 was covered by patents: WO 2013058691, etc.
