NMS-873

Alias: NMS-873; NMS873; NMS 873
Cat No.:V1318 Purity: ≥98%
NMS-873 (also known as NMS 873, NMS873, p97 inhibitor) is a potent, allosteric and specific p97 inhibitor with potential antitumor activity.
NMS-873 Chemical Structure CAS No.: 1418013-75-8
Product category: p97
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

NMS-873 (also known as NMS 873, NMS873, p97 inhibitor) is a potent, allosteric and specific p97 inhibitor with potential antitumor activity. With an IC50 value of 30 nM, it inhibits p97.

Biological Activity I Assay Protocols (From Reference)
Targets
p97 ( IC50 = 30 nM )
ln Vitro
NMS-873 inhibits the degradation of the linker-D2 domain by decreasing the sensitivity of p97 to trypsin digestion. Several hematological and solid tumor lines exhibit antiproliferative activity in response to NMS-873, a p97 inhibitor. According to the mechanism study, NMS-873 increases the unfolded protein response, obstructs autophagy, and ultimately causes the death of cancer cells.[1]
ln Vivo
NMS-873 exhibits cell-killing efficacy against a broad range of solid tumors with an IC50 range of 0.08μM to 2μM, in addition to hematological tumors.
Enzyme Assay
A modified NADH-coupled assay is used to monitor ADP formation in the reaction in order to assess the ATPase activity and kinetic parameters of recombinant wild-type VCP and its mutants. Given that both ADP and NADH are ATP-competitive inhibitors of VCP ATPase activity, the standard protocol for the NADH-coupled assay has been altered to occur in two steps. In the initial phase, an ATP-regenerating system consisting of 3 mM phosphoenolpyruvate and 40 U/ml pyruvate kinase recycles the ADP generated by VCP activity, maintains a constant substrate concentration to avoid product inhibition, and builds up a stoichiometric amount of pyruvate. The second section involves quenching the VCP enzymatic reaction with 30 mM EDTA and 250 μM NADH, followed by a stoichiometric oxidation by 40 U/ml lactic dehydrogenase, which lowers the pyruvate accumulation. A Tecan Safire 2 reader plate is used to measure the drop in NADH concentration at 340 nm. The assay is run in 96-or 384-well UV plates in a reaction buffer containing 2 mM DTT, 10 mM MgCl2, pH 7.5, 0.2 mg/mL BSA, and 50 mM Hepes. A cooperative equation is used to fit the experimental data, yielding a Ks* of roughly 60 μM and a Hill coefficient (n) of 2.0 ± 0.1. A more sensitive ADP detection system called Transcreener ADP FP is used in conjunction with a miniaturized assay in a 1,536-well format to conduct the HTS campaign against a library of one million compounds. After preincubating 10 μM inhibitor and 10 nM VCP for 20 minutes, 10 μM ATP is added to the reaction, which is then allowed to proceed for 90 minutes before quenching. With 3× s.d. (38% inhibition) as the cutoff, the screening average Z′ is 0.58, and the hit rate is 1.7%. Physicochemical and structural filters are used to remove primary hits that exhibit more than 60% inhibition at a concentration of 10 μM, leaving 7,516 compounds. Finally, 500 compounds are chosen for a dose-response analysis utilizing the previously mentioned NADH-modified coupled assay after reconfirmation is carried out in duplicate on 3,988 primary hits. The C522T mutant and wild-type VCP are used to gauge how potent the most intriguing HTS hits are. In the assay, ATP concentrations that produced the half-maximal velocity (Ks*) for each enzyme—60 μM for the wild type and 130 μM for the C522T mutant, respectively—are employed. In order to investigate the reversible inhibitors' dependence on substrate concentration, their potency is assessed at saturating ATP concentrations of 1 mM and juxtaposed with the potency of a conventional ATP competitive inhibitor (AMP-PNP).
Cell Assay
In 384-well white clear-bottom plates, 1,600 cells are seeded per well of the plate. The compounds are added to the cells twenty-four hours after they are seeded (eight dilution points, in duplicate, for each compound), and they are then incubated for a further 72 hours at 37°C with 5% CO2 in the air. After that, the cells are lysed, and a thermostable firefly luciferase-based assay from Promega is used to measure the amount of ATP present in each well as a proxy for cell viability. The percentage of treated cell growth compared to the untreated control is used to calculate IC50 values.
Animal Protocol


References

[1]. Covalent and allosteric inhibitors of the ATPATP ase VCP/p97 induce cancer cell death. Nat Chem Biol. 2013 Jul 28. doi: 10.1038/nchembio.1313.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C27H28N4O3S2
Molecular Weight
520.67
Exact Mass
520.16
Elemental Analysis
C, 62.28; H, 5.42; N, 10.76; O, 9.22; S, 12.32
CAS #
1418013-75-8
Appearance
White solid powder
SMILES
CC1=C(C=CC(=C1)OCC2=NN=C(N2C3=CN=CC=C3)SC4CCCC4)C5=CC=C(C=C5)S(=O)(=O)C
InChi Key
UJGTUKMAJVCBIS-UHFFFAOYSA-N
InChi Code
InChI=1S/C27H28N4O3S2/c1-19-16-22(11-14-25(19)20-9-12-24(13-10-20)36(2,32)33)34-18-26-29-30-27(35-23-7-3-4-8-23)31(26)21-6-5-15-28-17-21/h5-6,9-17,23H,3-4,7-8,18H2,1-2H3
Chemical Name
3-[3-cyclopentylsulfanyl-5-[[3-methyl-4-(4-methylsulfonylphenyl)phenoxy]methyl]-1,2,4-triazol-4-yl]pyridine
Synonyms
NMS-873; NMS873; NMS 873
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO : 20.5~100 mg/mL (9.4 ~192.1 mM)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 1.9206 mL 9.6030 mL 19.2060 mL
5 mM 0.3841 mL 1.9206 mL 3.8412 mL
10 mM 0.1921 mL 0.9603 mL 1.9206 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Note: Chemical formula is case sensitive: C12H18N3O4  c12h18n3o4
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Working concentration mg/mL;

Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.

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