1418013-75-8

Basic information

• Product Name: NMS 873
• Synonyms: NMS 873;NMS873;NMS-873;NMS873/NMS-873;Pyridine, 3-[3-(cyclopentylthio)-5-[[[2-methyl-4'-(methylsulfonyl)[1,1'-biphenyl]-4-yl]oxy]methyl]-4H-1,2,4-triazol-4-yl]-;3-[3-(Cyclopentylthio)-5-[[[2-methyl-4'-(methylsulfonyl)[1,1'-biphenyl]-4-yl]oxy]methyl]-4H-1,2,4-triazol-4-yl]pyridine NMS-873;NMS 873 3-[3-(Cyclopentylthio)-5-[[[2-methyl-4'-(methylsulfonyl)[1,1'-biphenyl]-4-yl]oxy]methyl]-4H-1,2,4-triazol-4-yl]pyridine;3-[3-Cyclopentylsulfanyl-5-(4′-methanesulfonyl-2-methylbiphenyl-4-yloxymethyl)-[1,2,4]triazol-4-yl]-pyridine
• CAS NO: 1418013-75-8
• Molecular Formula: C₂₇H₂₈N₄O₃S₂
• Molecular Weight: 520.68
• EINECS: 200-256-5
• Product Categories: Inhibitors;api
• Mol File: 1418013-75-8.mol
• Article Data: 1

Chemical Properties

• Boiling Point: 769.3±70.0 °C(Predicted)
• Appearance: white to beige/
• Density: 1.33±0.1 g/cm3(Predicted)
• Storage Temp.: 2-8°C
• Solubility: DMSO: soluble25mg/mL, clear
• PKA: 2.48±0.12(Predicted)
• CAS DataBase Reference: NMS 873(CAS DataBase Reference)
• NIST Chemistry Reference: NMS 873(1418013-75-8)
• EPA Substance Registry System: NMS 873(1418013-75-8)

Safety Data

• Hazard Codes: Xn
• Statements: 22
• WGK Germany: 3
• Hazardous Substances Data: 1418013-75-8(Hazardous Substances Data)

Usage

Description

The p97 AAA (ATPase associated with diverse cellular activities) is a ubiquitin-selective chaperone known to play a critical role in the degradation of misfolded membrane and secretory proteins and has been linked to various cellular processes that require unfolding and disassembly of protein complexes. Valosin-containing protein (VCP), also known as VCP/p97, is an AAA ATPase family member that serves as an integral component of the ubiquitin fusion degradation pathway and is overexpressed in many tumor types. NMS-873 is a VCP inhibitor (IC50 = 24 nM) that demonstrates potent selectivity for VCP/p97 compared to a panel of other AAA ATPases, Hsp90, and 53 additional analyzed kinases (IC50s >10 μM). It has been shown to inhibit the proliferation of HCT116 cancer cells with an IC50 value of 380 nM.

Uses

NMS-873 is a potent and specific VCP inhibitor, which has shown to activate the unfolded protein response, interfere with autophagy and induce cancer cell death.

Biochem/physiol Actions

NMS-873 is a selective allosteric non–ATP-competitive inhibitor of the AAA ATPase family member valosine containing protein (VCP), also known as p97 (VCP/p97), an integral component of the ubiquitin fusion degradation (UFD) pathway. VCP/p97 plays a role in degradation of misfolded proteins, Golgi membrane reassembly, membrane transport, myofibril assembly, autophagosome maturation, and cell division, and is overexpressed in many tumor types. NMS-873 is the most potent and specific VCP inhibitor described to date. NMS-873 has an IC50 of 30 nM for VCP/p97 compared to IC50 >10 μM against all of the AAA ATPases, HSP90 or the 53 kinases analyzed. NMS-873 inhibited proliferation of HCT116 cancer cell line cells with an IC50 value of 400 nM.

references

[1] magnaghi p, d'alessio r, valsasina b, avanzi n, rizzi s, asa d, gasparri f, cozzi l, cucchi u, orrenius c, polucci p, ballinari d, perrera c, leone a, cervi g, casale e, xiao y, wong c, anderson dj, galvani a, donati d, o'brien t, jackson pk, isacchi a. covalent and allosteric inhibitors of the atpase vcp/p97 induce cancer cell death. nat chem biol. 2013 sep;9(9):548-56. doi: 10.1038/nchembio.1313. epub 2013 jul 28.

Upstream product

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• 1418012-78-8 (5-cyclopentylsulfanyl-4-pyridin-3-yl-4H[1,2,4]triazol-3-yl)methanol 
• 1418012-77-7 3-(3-benzyloxymethyl-5-cyclopentylsulfanyl[1,2,4]triazol-4-yl)pyridine 

Relevant articles and documents

Alkylsulfanyl-1,2,4-triazoles, a New Class of allosteric valosine containing protein inhibitors. Synthesis and structure-activity relationships

Valosine containing protein (VCP), also known as p97, is a member of AAA ATPase family that is involved in several biological processes and plays a central role in the ubiquitin-mediated degradation of misfolded proteins. VCP is an ubiquitously expressed, highly abundant protein and has been found overexpressed in many tumor types, sometimes associated with poor prognosis. In this respect, VCP has recently received a great deal of attention as a potential new target for cancer therapy. In this paper, the discovery and structure-activity relationships of alkylsulfanyl-1,2,4-triazoles, a new class of potent, allosteric VCP inhibitors, are described. Medicinal chemistry manipulation of compound 1, identified via HTS, led to the discovery of potent and selective inhibitors with submicromolar activity in cells and clear mechanism of action at consistent doses. This represents a first step toward a new class of potential anticancer agents.