531088 VCP Inhibitor III, NMS-873 - CAS 1418013-75-8 - Calbiochem

531088
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Key Specifications Table

Empirical FormulaCAS #
C₂₇H₂₈N₄O₃S₂ 1418013-75-8

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      Description
      OverviewA cell-permeable triazolylpyridine compound that potently inhibits VCP ATPase activity in a non-ATP-competitive manner (IC50/[ATP] = 20 nM/1 mM & 30 nM/60 µM; [wt hVCP] = 10 nM) via an allosteric mechanism where the inhibitor targets the lateral tunnel formed by the D1 & D2 domains of one VCP protomer together with the D1 from the adjacent VCP molecule in the hexamer, effectively locking the protomer in a rigid conformation and thereby preventing the release of bound ADP for successful propagation of interprotomer ATP hydrolysis cycle, while being ineffective against a panel of 53 kinases or the ATPase activities of 4 other AAA (ATPase Associated with diverse/various cellular Activities) ATPases (NSF, SPATAS, VPS4B, and cdc6) and Hsp90 (by <15% at 10 µM). In agreement with siRNA-mediated VCP knockdown, NMS-873 is shown to prevent VCP from extracting ubiquitinated client proteins, including cyclin E & Mcl-1, for proteasomal degradation, resulting in cellular UPR (unfold protein response) activation, autophagy induction, and eventual apoptosis in HCT-116 cultures in a dose- and time-dependent manner (0.5 to 5 µM; 8 to 72 h). Anti-cancer studies using a panel of 40 various hematological and solid tumor lines reveal wide-spread sensitivities to NMS-873-induced killings (IC50 from 80 nM to 2 µM), differing in degrees than those observed with the proteasome inhibitor Bortezomib (Cat. No. Cat. No. 504314). Exhibits high clearance and low bioavailability in in vivo studies.

      Please note that the molecular weight for this compound is batch-specific due to variable water content.
      Catalogue Number531088
      Brand Family Calbiochem®
      Synonyms3-(3-(Cyclopentylthio)-5-((2-methyl-4ʹ-(methylsulfonyl)biphenyl-4-yloxy)methyl)-4H-1,2,4-triazol-4-yl)pyridine, 3-(3-Cyclopentylsulfanyl-5-(4ʹ-methanesulfonyl-2-methyl-biphenyl-4-yloxymethyl)-[1,2,4]triazol-4-yl)-pyridine, Valosin-containing Protein Inhibitor III, p97 Inhibitor III, ERAD Inhibitor III, NMS873
      References
      ReferencesMagnaghi, P., et al. 2013. Nat. Chem. Biol. 9, 548.
      Polucci, P., et al. 2013. J. Med. Chem. 56, 437.
      Product Information
      CAS number1418013-75-8
      FormLight beige powder
      Hill FormulaC₂₇H₂₈N₄O₃S₂
      Chemical formulaC₂₇H₂₈N₄O₃S₂
      ReversibleY
      Quality LevelMQ100
      Applications
      Biological Information
      Primary TargetVCP
      Purity≥98% 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 +2°C to +8°C
      Protect from Light Protect from light
      Do not freeze Ok to freeze
      Special InstructionsFollowing reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.
      Packaging Information
      Packaged under inert gas Packaged under inert gas
      Transport Information
      Supplemental Information
      Specifications

      Documentation

      VCP Inhibitor III, NMS-873 - CAS 1418013-75-8 - Calbiochem SDS

      Title

      Safety Data Sheet (SDS) 

      References

      Reference overview
      Magnaghi, P., et al. 2013. Nat. Chem. Biol. 9, 548.
      Polucci, P., et al. 2013. J. Med. Chem. 56, 437.
      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.

      Revision31-July-2014 JSW
      Synonyms3-(3-(Cyclopentylthio)-5-((2-methyl-4ʹ-(methylsulfonyl)biphenyl-4-yloxy)methyl)-4H-1,2,4-triazol-4-yl)pyridine, 3-(3-Cyclopentylsulfanyl-5-(4ʹ-methanesulfonyl-2-methyl-biphenyl-4-yloxymethyl)-[1,2,4]triazol-4-yl)-pyridine, Valosin-containing Protein Inhibitor III, p97 Inhibitor III, ERAD Inhibitor III, NMS873
      DescriptionA cell-permeable triazolylpyridine compound that potently inhibits VCP ATPase activity in a non-ATP-competitive manner (IC50/[ATP] = 20 nM/1 mM & 30 nM/60 µM; [wt hVCP] = 10 nM) via an allosteric mechanism where the inhibitor targets the lateral tunnel formed by the D1 & D2 domains of one VCP protomer together with the D1 from the adjacent VCP molecule in the hexamer, effectively locking the protomer in a rigid conformation and thereby preventing the release of bound ADP for successful propagation of interprotomer ATP hydrolysis cycle, while being ineffective against a panel of 53 kinases or the ATPase activities of 4 other AAA (ATPase Associated with diverse/various cellular Activities) ATPases (NSF, SPATAS, VPS4B, and cdc6) and Hsp90 (by <15% at 10 µM). In agreement with siRNA-mediated VCP knockdown, NMS-873 is shown to prevent VCP from extracting ubiquitinated client proteins, including cyclin E & Mcl-1, for proteasomal degradation, resulting in cellular UPR (unfold protein response) activation, autophagy induction, and eventual apoptosis in HCT-116 cultures in a dose- and time-dependent manner (0.5 to 5 µM; 8 to 72 h). Anti-cancer studies using a panel of 40 various hematological and solid tumor lines reveal wide-spread sensitivities to NMS-873-induced killings (IC50 from 80 nM to 2 µM), differing in degrees than those observed with the proteasome inhibitor Bortezomib (Cat. No. Cat. No. 504314). Exhibits high clearance and low bioavailability in in vivo studies.
      FormLight beige powder
      Intert gas (Yes/No) Packaged under inert gas
      CAS number1418013-75-8
      Chemical formulaC₂₇H₂₈N₄O₃S₂
      Purity≥98% by HPLC
      Storage +2°C to +8°C
      Protect from light
      Do Not Freeze Ok to freeze
      Special InstructionsFollowing reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.
      Toxicity Standard Handling
      ReferencesMagnaghi, P., et al. 2013. Nat. Chem. Biol. 9, 548.
      Polucci, P., et al. 2013. J. Med. Chem. 56, 437.