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5.30341

Sigma-Aldrich

RPN13 Inhibitor, RA190

Sinonimo/i:

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

Formula empirica (notazione di Hill):
C28H22Cl4N2O2 · xHCl
Numero CAS:
Peso molecolare:
560.30 (free base basis)
Codice UNSPSC:
12352200
ID PubChem:
NACRES:
NA.77

Saggio

≥97% (HPLC)

Livello qualitativo

Stato

solid

Produttore/marchio commerciale

Calbiochem®

Condizioni di stoccaggio

OK to freeze
desiccated (hygroscopic)
protect from light

Colore

yellow

Solubilità

water: 5 mg/mL
DMSO: 50 mg/mL

Temperatura di conservazione

−20°C

Stringa SMILE

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

Descrizione generale

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.

Azioni biochim/fisiol

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

Attenzione

Toxicity: Standard Handling (A)

Ricostituzione

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

Altre note

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

Note legali

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

Codice della classe di stoccaggio

11 - Combustible Solids

Classe di pericolosità dell'acqua (WGK)

WGK 3

Punto d’infiammabilità (°F)

Not applicable

Punto d’infiammabilità (°C)

Not applicable


Certificati d'analisi (COA)

Cerca il Certificati d'analisi (COA) digitando il numero di lotto/batch corrispondente. I numeri di lotto o di batch sono stampati sull'etichetta dei prodotti dopo la parola ‘Lotto’ o ‘Batch’.

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