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Merck
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主要文書

5.30341

Sigma-Aldrich

RPN13 Inhibitor, RA190

別名:

RPN13 Inhibitor, RA190, 3,5- bis(3,4-Dichlorobenzylidene)-1-( S-2-amino-3-phenyl)-piperidin-4-one, HCl, ADRM1 Inhibitor, Adhesion Regulating Molecule 1 Inhibitor, ARM1 Inhibitor; GP110 Inhibitor

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About This Item

実験式(ヒル表記法):
C28H22Cl4N2O2 · xHCl
CAS番号:
分子量:
560.30 (free base basis)
UNSPSCコード:
12352200
PubChem Substance ID:
NACRES:
NA.77

アッセイ

≥97% (HPLC)

品質水準

フォーム

solid

メーカー/製品名

Calbiochem®

保管条件

OK to freeze
desiccated (hygroscopic)
protect from light

yellow

溶解性

water: 5 mg/mL
DMSO: 50 mg/mL

保管温度

−20°C

SMILES記法

C1C(=CC2=CC(=C(C=C2)Cl)Cl)C(=O)C(=CC3=CC(=C(C=C3)Cl)Cl)CN1C(=O)C(CC4=CC=CC=C4)N.Cl

InChI

1S/C28H22Cl4N2O2.ClH/c29-22-8-6-18(12-24(22)31)10-20-15-34(28(36)26(33)14-17-4-2-1-3-5-17)16-21(27(20)35)11-19-7-9-23(30)25(32)13-19;/h1-13,26H,14-16,33H2;1H

詳細

A cell-permeable bis-benzylidine piperidone that covalently modifies RPN13/ADRM1 via Michael addition between its electrophilic enone and the nucleophilic RPN13 Cys88, most likely freeing pleckstrin-like receptor for ubiquitin (Pru) domain from intramolecular interaction with the UCH37-binding domain and thereby allowing non-proteasome-associated RPN13 to compete against proteasome 19S regulatory particle- (RP-) incorporated RPN13 for ubiquitinated substrates binding, without affecting RPN13 RP assembly, 20S core particle (CP) proteolytic activities, or the deubiquitinase activity of UCH37 or RP. RPN13 blockage not only prevents many pro-apoptotic factors from degradation, the buildup of cellular ubiquitinated proteins in general also effectively triggers ER unfold protein response (UPR), accounting for the observed RA190 anticancer activity, notably in Multiple Myeloma (IC50 in nM = 35/MM.1S, 50/NCI-H929, 75/ANBL6,100/RPMI-8226), HPV+ cervical cancer (IC50 in nM = 150/HeLa, 300/CasKi, 750/HiHa), and HPV16-transformed oral keratinocyte HOK-16B (IC50 = 600 nM) cultures. RA190 is bioavailable via either oral or intraperitoneal administration in mice with tissue distribution in blood and major organs except brain and effectively inhibits NCI-H929 (20 mg/kg/d, i.p.), ES-2 (10 mg/kg/d, i.p.), and TC-1 (40 mg/kg/72 h, p.o.) tumor growths, as well as prevents 4UbFL reporter degradation in skin via topical application in mice in vivo without signs of adverse effects to animals or compromised host immune response. Synergizes with the 20S CP proteolytic activity inhibitor Bortezomib (Cat. No. 504314) in HeLa killing and is active against Bortezomib-resistant RPMI-8226-V10R and ANBL6-V10R cultures.
A cell-permeable, bioavailable, non-toxic bis-benzylidine piperidone compound that directly and covalently binds to Cys88 of ubiquitin receptor RPN13 Pru domain (pleckstrin-like receptor for ubiquitin) in the 19S regulatory particle and inhibits proteasome function leading to rapid accumulation of polyubiquitinated proteins. Does not affect the chymotryptic, tryptic, and peptidyl-glutamyl peptide-hydrolyzing activities of the 20S core particle. Exhibits anti-proliferative effects against multiple myeloma cells (IC50 = 100 nM) and HPV transformed cells (IC50 = 300 nM). Acts synergistically with bortezomib (Cat. No. 504314) to diminish cervical cancer cell viability and is effective even in multiple myeloma cells that are resistant to bortezomib treatment. Elevates p53 and p53-regulated genes in HeLa, CaSki, and SiHa cervical cancer cells as observed with bortezomib. Shown to induce apoptosis via induction of endoplasmic reticulum stress and up-regulate ATF-4 protein and CHOP-10 and XBP1s mRNA levels prior to apoptosis in MM.1S and HeLa cells. Reduces the growth of multiple myeloma and ovarian cancer xenografts in mice without affecting spontaneous HPV-specific CD8+ T cell responses. Displays desirable pharmacokinetic properties with Cmax in about 2 hours and t1/2α = 4.2 h; t1/2β = 25.5 h following a 10 mg/kg dose (i.p).

Please note that the molecular weight for this compound is batch-specific due to variable water content. Please refer to the vial label or the certificate of analysis for the batch-specific molecular weight. The molecular weight provided represents the baseline molecular weight without water.
RPN13 Inhibitor, RA190, is a cell-permeable compound that binds to cysteine 88 of ubiquitin receptor RPN13 Pru domain in the 19S regulatory particle and inhibits proteasome function.

生物化学的/生理学的作用

Cell permeable: yes
Primary Target
RPN13/ADRM1
Reversible: no

警告

Toxicity: Standard Handling (A)

再構成

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 3 months at -20°C.
Use only fresh DMSO for reconstitution

その他情報

Anchoori, R.K., et al. 2013. Cancer Cell.24, 791.

法的情報

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

保管分類コード

11 - Combustible Solids

WGK

WGK 3

引火点(°F)

Not applicable

引火点(℃)

Not applicable


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関連コンテンツ

Select different protease inhibitor types based on your needs to prevent protein degradation during isolation and characterization and safeguard proteins in sample prep.

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