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b-AP15

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Chemical Structure| 1009817-63-3 同义名 : NSC 687852
CAS号 : 1009817-63-3
货号 : A619221
分子式 : C22H17N3O6
纯度 : 98%
分子量 : 419.387
MDL号 : MFCD26142662
存储条件：

粉末 Sealed in dry,2-8°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 18 mg/mL(42.92 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

4% DMSO+corn oil 1 mg/mL

生物活性
靶点

  • UCH

    UCHL5, IC50:2.1 μM
描述 The ubiquitin-specific peptidases (USPs) are the main members of the deubiquitinase(DUB) family. b-AP15 is an inhibitor of 19S proteasome deubiquitinase (DUB) with IC50 value of 6.5 μM[3]. In vitro, b-AP15 induced time- and dose-dependent apoptosis of the human multiple myeloma cell lines RPM18226 and U266. b-AP15 triggered processing of pro-caspase-3 and cleavage of ploy (ADP-ribose) polymerase in the human multiple myeloma cell. b-AP15 also induced caspase-independent apoptosis in primary human natural killer cells[4]. In vivo, administration of b-AP15 at 4 mg/kg once daily for 14 days was well tolerated, inhibited tumor growth, and prolong survival in human multiple myeloma xenograft models[5]. Treatment with b-AP15 at dose of 5 mg/kg inhibited tumor growth in SCID mice with FaDu human tumor xenograft and C57BL/6J mice with Lewis lung carcinomas (LLCs). Treatment with b-AP15 at dose of 2.5 mg/kg also inhibited tumor growth in BALB/c mice with orthotopic breast carcinoma. In addition, b-AP15 can inhibited organ infiltration in an acute myeloid leukemia model[6].
作用机制 b-AP15 blocks the DUB activity of the 19S regulatory particle (19S RP) without inhibiting the proteolytic activities of the 20S core particle (20S CP), and inhibits two proteasome-associated DUBs, USP14 and UCHL5, resulting in a rapid accumulation of high molecular weight ubiquitin conjugates and a functional proteasome shutdown[7].
细胞研究
细胞系 浓度 检测类型 检测时间 活动说明 数据源
CEM cells Cytotoxicity assay Cytotoxicity against human CEM cells, IC50=0.26 μM 19819135
HL60 cells Cytotoxicity assay Cytotoxicity against human HL60 cells in presence of RPMI1640 containing 10% fetal bovine serum by trypan blue exclusion test, CC50=0.13 μM 17499885
HSC4 cells Cytotoxicity assay Cytotoxicity against human HSC4 cells by MTT method, CC50=0.56 μM 17499885
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.38mL

0.48mL

0.24mL

11.92mL

2.38mL

1.19mL

23.84mL

4.77mL

2.38mL
参考文献

[1]Lopez-Castejon G, Luheshi NM, et al. Deubiquitinases regulate the activity of caspase-1 and interleukin-1β secretion via assembly of the inflammasome. J Biol Chem. 2013 Jan 25;288(4):2721-33.

[2]D'Arcy P, Brnjic S, et al. Inhibition of proteasome deubiquitinating activity as a new cancer therapy. Nat Med. 2011 Nov 6;17(12):1636-40.

[3]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.

[4]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. 2014 Mar;42(3):172-82.

[5]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.

[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.

[7]D'Arcy P, Linder S. Proteasome deubiquitinases as novel targets for cancer therapy. Int J Biochem Cell Biol. 2012 Nov;44(11):1729-38.