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VLX1570

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Chemical Structure| 1431280-51-1 同义名 : -
CAS号 : 1431280-51-1
货号 : A150004
分子式 : C23H17F2N3O6
纯度 : 99%+
分子量 : 469.394
MDL号 : MFCD28502165
存储条件：

粉末 Sealed in dry,Store in freezer, under -20°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 30 mg/mL(63.91 mM)，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：
生物活性
靶点

  • DUB

    DUB, IC50:~10 μM
描述 Deubiquitinating enzymes (DUBs) are key components of the ubiquitin-dependent protein degradation pathway and act as master regulators in a number of metabolic processes including cell growth, differentiation, and apoptosis[3]. VLX1570 is a competitive inhibitor of proteasome DUB activity with IC50 value of 10 μM. In vitro, VLX1570 induced the accumulation of proteasome-bound high molecular weight polyubiquitin conjugates and an apoptotic response. Inhibition of USP14 activity could be demonstrated in cells exposed to 0.5 μM VLX1570 whereas UCHL5 inhibition was weak in comparison. VLX1570 inhibited multiple myeloma cells proliferation, including KMS-11, RPMI8226, OPM-2 and OPM-2-BZR cell lines, with IC50 values ranging in 43 – 191 nM[4]. In addition, VLX1570 inhibited cell viability of ALL cell lines including 697, Reh, SEM, RS4;11, SUP-B15, CCRF-CEM and T-ALL cell lines, with IC50 values ranging in 50 - 100 nM, suggesting its highly sensitive to acute lymphoblastic leukemia cells[5]. In vivo, administered VLX1570 at 4.0 mg/kg via intraperitoneal injection every alternate day for 20 days resulted in decreased tumor burden and prolonged survival in waldenstrom macroglobulinemia tumor xenografted mice[6]. Treatment of a xenograft mouse model of ewing sarcoma (EWS) with VLX1570 at dose of 4.4 mg/kg once daily via intraperitoneal administration for 2 weeks significantly inhibited in vivo tumor growth[7].
作用机制 VLX1570 interferes with the proteasomal degradation by inhibiting the activities of the proteasomal DUBs USP14 and UCHL5[5].
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.13mL

0.43mL

0.21mL

10.65mL

2.13mL

1.07mL

21.30mL

4.26mL

2.13mL
参考文献

[1]Paulus A, Akhtar S, et al. 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.

[2]Wang X, Mazurkiewicz M, et al. 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.

[3]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.

[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.

[5]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.

[6]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.

[7]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.