Synonym
b-AP15; b-AP15; b-AP-15; USP14 Inhibitor III; UCHL5UCH37 Inhibitor II; NSC687852.
IUPAC/Chemical Name
(3E,5E)-1-acryloyl-3,5-bis(4-nitrobenzylidene)piperidin-4-one.
InChi Key
GFARQYQBWJLZMW-JYFOCSDGSA-N
InChi Code
InChI=1S/C22H17N3O6/c1-2-21(26)23-13-17(11-15-3-7-19(8-4-15)24(28)29)22(27)18(14-23)12-16-5-9-20(10-6-16)25(30)31/h2-12H,1,13-14H2/b17-11+,18-12+
SMILES Code
O=C1/C(CN(C(C=C)=O)C/C1=C\C2=CC=C([N+]([O-])=O)C=C2)=C/C3=CC=C([N+]([O-])=O)C=C3
Appearance
Yellow 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:
b-AP15 is a specific inhibitor of the deubiquitinating enzymes UCHL5 and Usp14.
In vitro activity:
Purified 19S proteasomes (5 nM) are treated with indicated concentrations of b-AP15 and DUB activity is determined by detectionof Ub-AMC cleavage. The IC50 value (2.1±0.411 μM) is determined from log concentration curves in Graph Pad Prism using non linear regression analysis. b-AP15 as a previously unidentified class of proteasome inhibitor that abrogates the deubiquitinating activity of the 19S regulatory particle. b-AP15 inhibited the activity of two 19S regulatory-particle-associated deubiquitinases, ubiquitin C-terminal hydrolase 5 (UCHL5) and ubiquitin-specific peptidase 14 (USP14), resulting in accumulation of polyubiquitin. b-AP15 induced tumor cell apoptosis that is insensitive to TP53 status and overexpression of the apoptosis inhibitor BCL2.
Reference: Nat Med. 2011 Nov 6;17(12):1636-40. https://doi.org/10.1038/nm.2536
In vivo activity:
b-AP15 (2.5 mg/kg) inhibits tumor growth in syngenic mice models with less frequent administration schedules. We administered b-AP15 to C57BL/6J mice with Lewis lung carcinomas (LLCs) using a 2-d-on, 2-d-off schedule and to BALB/c mice with orthotopic breast carcinoma (4T1) using a 1-d-on, 3-d-off schedule. b-AP15 significantly inhibited tumor growth in both models, with T/C=0.16 (P≤0.01) for the C57BL/6J mice and T/C=0.25 (P≤0.001) for the BALB/c mice. A reduction in the number of pulmonary metastases also is observed in the group of mice with 4T1 breast carcinomas treated with b-AP15.
Reference: Nat Med. 2011 Nov 6;17(12):1636-40. https://doi.org/10.1038/nm.2536
|
Solvent |
mg/mL |
mM |
| Solubility |
| DMSO |
20.0 |
47.69 |
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
419.39
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 |
In vitro protocol:
1. D'Arcy P, Brnjic S, Olofsson MH, Fryknäs M, Lindsten K, De Cesare M, Perego P, Sadeghi B, Hassan M, Larsson R, Linder S. Inhibition of proteasome deubiquitinating activity as a new cancer therapy. Nat Med. 2011 Nov 6;17(12):1636-40. doi: 10.1038/nm.2536. PMID: 22057347.
2. Tian Z, D'Arcy P, Wang X, Ray A, Tai YT, Hu Y, Carrasco RD, Richardson P, Linder S, Chauhan D, Anderson KC. A novel small molecule inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance. Blood. 2014 Jan 30;123(5):706-16. doi: 10.1182/blood-2013-05-500033. Epub 2013 Dec 6. PMID: 24319254; PMCID: PMC3907756.
In vivo protocol:
1. D'Arcy P, Brnjic S, Olofsson MH, Fryknäs M, Lindsten K, De Cesare M, Perego P, Sadeghi B, Hassan M, Larsson R, Linder S. Inhibition of proteasome deubiquitinating activity as a new cancer therapy. Nat Med. 2011 Nov 6;17(12):1636-40. doi: 10.1038/nm.2536. PMID: 22057347.
1: Tian Z, D'Arcy P, Wang X, Ray A, Tai YT, Hu Y, Carrasco RD, Richardson P, Linder S, Chauhan D, Anderson KC. A novel small molecule inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance. Blood. 2014 Jan 30;123(5):706-16. doi: 10.1182/blood-2013-05-500033. Epub 2013 Dec 6. PubMed PMID: 24319254.
2: Feng X, Holmlund T, Zheng C, Fadeel B. Proapoptotic effects of the novel proteasome inhibitor b-AP15 on multiple myeloma cells and natural killer cells. Exp Hematol. 2013 Nov 27. pii: S0301-472X(13)00871-0. doi: 10.1016/j.exphem.2013.11.010. [Epub ahead of print] PubMed PMID: 24291587.
3: Brnjic S, Mazurkiewicz M, Fryknäs M, Sun C, Zhang X, Larsson R, D'Arcy P, Linder S. Induction of Tumor Cell Apoptosis by a Proteasome Deubiquitinase Inhibitor Is Associated with Oxidative Stress. Antioxid Redox Signal. 2013 Oct 17. [Epub ahead of print] PubMed PMID: 24011031.
4: Sarhan D, Wennerberg E, D'Arcy P, Gurajada D, Linder S, Lundqvist A. A novel inhibitor of proteasome deubiquitinating activity renders tumor cells sensitive to TRAIL-mediated apoptosis by natural killer cells and T cells. Cancer Immunol Immunother. 2013 Aug;62(8):1359-68. doi: 10.1007/s00262-013-1439-1. Epub 2013 May 21. PubMed PMID: 23689729.
5: D'Arcy P, Linder S. Proteasome deubiquitinases as novel targets for cancer therapy. Int J Biochem Cell Biol. 2012 Nov;44(11):1729-38. doi: 10.1016/j.biocel.2012.07.011. Epub 2012 Jul 20. Review. PubMed PMID: 22819849.
6: D'Arcy P, Brnjic S, Olofsson MH, Fryknäs M, Lindsten K, De Cesare M, Perego P, Sadeghi B, Hassan M, Larsson R, Linder S. Inhibition of proteasome deubiquitinating activity as a new cancer therapy. Nat Med. 2011 Nov 6;17(12):1636-40. doi: 10.1038/nm.2536. PubMed PMID: 22057347.
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