530341 RPN13 Inhibitor, RA190 - Calbiochem

530341
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      Overview

      Replacement Information

      Key Specifications Table

      Empirical Formula
      C₂₈H₂₂Cl₄N₂O₂ •HCl

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      5.30341.0001
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          Glass bottle 10 mg
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          Description
          OverviewA 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.
          Catalogue Number530341
          Brand Family Calbiochem®
          Synonyms3,5-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
          References
          ReferencesAnchoori, R.K., et al. 2013. Cancer Cell. 24, 791.
          Product Information
          FormYellow solid
          Hill FormulaC₂₈H₂₂Cl₄N₂O₂ •HCl
          Chemical formulaC₂₈H₂₂Cl₄N₂O₂ •HCl
          Hygroscopic Hygroscopic
          ReversibleN
          Applications
          Biological Information
          Primary TargetRPN13/ADRM1
          Purity≥97% by HPLC
          Physicochemical Information
          Cell permeableY
          Dimensions
          Materials Information
          Toxicological Information
          Safety Information according to GHS
          Safety Information
          Product Usage Statements
          Storage and Shipping Information
          Ship Code Ambient Temperature Only
          Toxicity Standard Handling
          Storage -20°C
          Protect from Light Protect from light
          Hygroscopic Hygroscopic
          Do not freeze Ok to freeze
          Special InstructionsFollowing reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 3 months at -20°C.
          Packaging Information
          Packaged under inert gas Packaged under inert gas
          Transport Information
          Supplemental Information
          Specifications

          Documentation

          RPN13 Inhibitor, RA190 - Calbiochem SDS

          Title

          Safety Data Sheet (SDS) 

          References

          Reference overview
          Anchoori, R.K., et al. 2013. Cancer Cell. 24, 791.
          Data Sheet

          Note that this data sheet is not lot-specific and is representative of the current specifications for this product. Please consult the vial label and the certificate of analysis for information on specific lots. Also note that shipping conditions may differ from storage conditions.

          Revision20-November-2015 JSW
          Synonyms3,5-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
          DescriptionA 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.
          FormYellow solid
          Intert gas (Yes/No) Packaged under inert gas
          Chemical formulaC₂₈H₂₂Cl₄N₂O₂ •HCl
          Purity≥97% by HPLC
          SolubilityDMSO (50 mg/ml). Use only fresh DMSO for reconstitution. Only sparingly soluble in water (5 mg/ml).
          Storage -20°C
          Hygroscopic
          Protect from light
          Do Not Freeze Ok to freeze
          Special InstructionsFollowing reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 3 months at -20°C.
          Toxicity Standard Handling
          ReferencesAnchoori, R.K., et al. 2013. Cancer Cell. 24, 791.