SNX-2112

Catalog No.S2639 Batch:S263901

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Technical Data

Formula

C23H27F3N4O3
Molecular Weight 464.48 CAS No. 908112-43-6
Solubility (25°C)* In vitro DMSO 93 mg/mL (200.22 mM)
Ethanol 1 mg/mL (2.15 mM)
Water Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description SNX-2112 selectively binds to the ATP pocket of HSP90α and HSP90β with Ka of 30 nM and 30 nM, uniformly more potent than 17-AAG.
Targets
HSP90α [1]
(cell-free assay)		 HSP90β [1]
(cell-free assay)
30 nM(Ka) 30 nM(Ka)
In vitro Treatment of BT-474 cells with 1 μM SNX-2112 results in down-regulation of HER2 expression within 3 to 6 hours of drug exposure with near-complete loss of HER2 expression by 10 hours. Treatment with SNX-2112 also results in a decline in total Akt expression. SNX-2112 inhibits cell proliferation with IC50 values ranging from 10 to 50 nM, in BT474, SKBR-3, SKOV-3, MDA-468, MCF-7 and H1650 cancer cells. And these antiproliferative effects are associated with hypophosphorylation of Rb, arrest of G1 and modest levels of apotosis. [1] SNX-2112 competitively binds to the N-terminal adenosine triphosphate binding site of Hsp90. SNX-2112 induces apoptosis via caspase-8, -9, -3, and poly (ADPribose) polymerase cleavage. SNX-2112 inhibits cytokine-inducedAkt and extracellular signal-related kinase (ERK) activation and also overcomes the growth advantages conferred by interleukin-6, insulin-like growth factor-1, and bone marrow stromal cells. SNX-2112 inhibits tube formation by human umbilical vein endothelial cells via abrogation of eNOS/Akt pathway and markedly inhibits osteoclast formation via down-regulation of ERK/c-fos and PU.1. [2] Cell lines (eight cell lines from osteosarcoma, neuroblastoma, hepatoblastoma, and ymphoma) studied demonstrates sensitivity to SNX-2112 with IC50 values ranging from 10-100 nM. A higher dose (70 nM) exhibits a more prolonged inhibition and larger sub-G1 accumulation. Observed levels of Akt1 and C-Raf are markedly reduced over time along with an increase in PARP cleavage. [3] A recent research indicates NX-2112 induces autophagy in a time- and dose-dependent manner via Akt/mTOR/p70S6K inhibition. SNX-2112 induces significant apoptosis and utophagy in human melanoma A-375 cells, and may be an effective targeted therapy agent. [4]
In vivo SNX-2112, delivered by its prodrug SNX-5422, inhibits MM cell growth and prolongs survival in a xenograft murine model and blockade of Hsp90 by SNX-2112 not only inhibits MM cell growth but also acts in the bone marrow microenvironment to block angiogenesis and osteoclastogenesis. [2]

Protocol (from reference)

Kinase Assay:[1]
  • ATP Displacement Assay

    For the protein affinity-displacement assay, a purine-based affinity resin is generated by incubating ATP-linked Sepharose with Jurkat cell lysate (flash frozen and homogenized in saline) at 4 °C. This is then incubated with SNX-2112 for 90 minutes. Proteins eluted by drug are then resolved by SDS-PAGE, visualized with silver staining, and excised from the gel for MS-based identification. Briefly, after destaining and trypsin digestion, peptides are extracted with μC18 ZipTips and then eluted and spotted directly to a conventional stainless steel matrix-assisted laser desorption/ionization target with a saturated solution of α-cyano-4- hydroxycinnamic acid in 50% acetonitrile, 0.15% formic acid. Mass spectra are then acquired using a MALDI-TOF/TOF 4700 Proteomics Analyzer. MS spectra are acquired (1,000 shots per spectrum), and the three peaks from each with the greatest signal-to-noise ratio are automatically submitted for tandem MS analysis (3000 shots per spectrum). The collision energy is 1keV. Air is used as the collision gas. Protein identification is done from the MS and tandem MS data using GPS Explorer software with the integrated Mascot database search engine.

Cell Assay:[1]
  • Cell lines

    BT474, SKBR-3, SKOV-3, MDA-468, MCF-7 and H1650 cancer cells

  • Concentrations

    0-500 nM

  • Incubation Time

    24 hours

  • Method

    Cell viability is determined by seeding 2-5 × 103 cells per well in 96- well plates and treating with SNX-2112 24 hours after plating in complete medium (200 μL). Each drug concentration is tested in eight wells. Cells are assayed using the Alamar blue viability test after a 96-h incubation. Flow cytometry is done using nuclei stained with ethidium bromide and isolated via the Nusse protocol
Animal Study:[2]
  • Animal Models

    5 × 106 MM.1S cells are inoculated subcutaneously in the Fox Chase SCID mice (6-7 weeks old).

  • Dosages

    20 or 40 mg/kg

  • Administration

    SNX-5422 is administered orally 3 times per week, total 3 weeks.

Customer Product Validation

Data from [Mol Cell Biol, 2013, 33(12), 2375-87]

Selleck's SNX-2112 has been cited by 13 publications

ERα-LBD, an isoform of estrogen receptor alpha, promotes breast cancer proliferation and endocrine resistance [ NPJ Breast Cancer, 2022, 8(1):96] PubMed: 35999225
deepOrganoid: A brightfield cell viability model for screening matrix-embedded organoids [ SLAS Discov, 2022, 27(3):175-184] PubMed: 35314378
Evolution of kinase polypharmacology across HSP90 drug discovery [ Cell Chem Biol, 2021, S2451-9456(21)00221-X] PubMed: 34077750
Antitumorigenic Effect of Hsp90 Inhibitor SNX-2112 on Tongue Squamous Cell Carcinoma is Enhanced by Low-Intensity Ultrasound [ Onco Targets Ther, 2020, 13:7907-7919] PubMed: 32884285
Click chemistry-facilitated comprehensive identification of proteins adducted by antimicrobial 5-nitroimidazoles for discovery of alternative drug targets against giardiasis. [ PLoS Negl Trop Dis, 2020, 17;14(4):e0008224] PubMed: 32302296
Structural basis for species-selective targeting of Hsp90 in a pathogenic fungus. [ Nat Commun, 2019, 10(1):402] PubMed: 30679438
Verteporfin blocks Clusterin which is required for survival of gastric cancer stem cell by modulating HSP90 function. [ Int J Biol Sci, 2019, 15(2):312-324] PubMed: 30745823
SNX-2112 Induces Apoptosis and Autophagy of Nara-H Cells [ Anticancer Res, 2018, 38(9):5177-5181] PubMed: 30194165
Predicting potential antitumor targets of Aconitum alkaloids by molecular docking and protein–ligand interaction fingerprint [Wael A, et al. Medicinal Chemistry Research, 2016, 10.1007/s00044-016-1553-7]
Heat shock protein 90 inhibitors induce functional inhibition of human natural killer cells in a dose-dependent manner [Huyan T, et al. Immunopharmacol Immunotoxicol, 2015, 8:1-10] PubMed: 26642940

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

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