AMG-900

Catalog No.S2719 Batch:S271904

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Technical Data

Formula

C28H21N7OS

Molecular Weight 503.58 CAS No. 945595-80-2
Solubility (25°C)* In vitro DMSO 100 mg/mL (198.57 mM)
Water Insoluble
Ethanol 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.)

Preparing Stock Solutions

Biological Activity

Description AMG 900 is a potent and highly selective pan-Aurora kinases inhibitor for Aurora A/B/C with IC50 of 5 nM/4 nM /1 nM. It is >10-fold selective for Aurora kinases than p38α, Tyk2, JNK2, Met and Tie2. Phase 1.
Targets
Aurora C [1]
(Cell-free assay)
Aurora B [1]
(Cell-free assay)
Aurora A [1]
(Cell-free assay)
p38α [1]
(Cell-free assay)
1 nM 4 nM 5 nM 53 nM
In vitro

AMG 900 is a novel class of ATP-competitive phthalazinamine small molecule inhibitors of aurora kinases. In HeLa cells, AMG 900 inhibits autophosphorylation of aurora-A and -B as well as phosphorylation of histone H3 on Ser, a proximal substrate of aurora-B. The predominant cellular response of tumor cells to AMG 900 treatment is aborted cell division without a prolonged mitotic arrest, which ultimately results in cell death. AMG 900 inhibits the proliferation of 26 tumor cell lines, including cell lines resistant and to other aurora kinase inhibitors (AZD1152, MK-0457, and PHA-739358), at low nanomolar concentrations (about 2- 3 nM). Furthermore, AMG 900 is active in an AZD1152-resistant HCT116 variant cell line that harbors an aurora-B mutation (W221L). [1]

In vivo

Oral administration of AMG 900 blocks the phosphorylation of histone H3 in a dose-dependent manner and significantly inhibited the growth of HCT116 tumor xenografts. AMG 900 is broadly active in multiple xenograft models, including 3 multidrugresistant xenograft models, representing 5 tumor types. [1] AMG 900 exhibits a low-to-moderate clearance and a small volume of distribution. Its terminal elimination half-life ranged from 0.6 to 2.4 hours. AMG 900 is well-absorbed in fasted animals with an oral bioavailability of 31% to 107%. Food intake has an effect on rate (rats) or extent (dogs) of AMG 900 oral absorption. The clearance and volume of distribution at steady state in humans are predicted to be 27.3 mL/h/kg and 93.9 mL/kg, respectively. AMG 900 exhibits acceptable PK properties in preclinical species and is predicted to have low clearance in humans. [2]

Protocol (from reference)

Kinase Assay:

[1]

  • Enzyme kinase assays

    Recombinant GST- or His-tagged aurora-A (TPX2), and aurora-B proteins are expressed using a baculovirus system and purified by affinity chromatography. AMG 900 activity is assessed using a standardized homogenous time-resolved fluorescence (HTRF) assay. Enzyme assays for 24 other kinases (aurora-C, p38α, TYK2, JNK2, JAK3, c-Met, VEGFR2, p38β, TIE-2, ABL (T315I), ERK1, BTK, JNK3, CDK5, PKAα, JNK1, p70S6K, PKBα, MSK1, LCK, SRC, IGFR, JAK2, and c-KIT) are done internally in a similar manner. Concentrations of enzyme, peptide substrate, and ATP in the reaction are optimized depending on the specific activity of the kinase and measured Km values for their corresponding substrates. AMG 900 is evaluated in a kinome competition binding assay (n = 353 unique kinases) by Ambit Biosciences. AMG 900 is initially screened at a single concentration of 1000 nM, and quantitative binding constants (Kd) are determined for each positive hit (< 20 percentage of control).

Cell Assay:

[1]

  • Cell lines

    Different tumor cell lines including NCI-H460, MDA-MB231, MES-SA, NCI-H460 PTX, MDA-MB-231 PTX, MES-SA Dx5, and HCT-15.

  • Concentrations

    0.5, 5.0, 50 nM

  • Incubation Time

    48 hours

  • Method

    Tumor cells are treated with AMG 900 for 48 hours, washed twice with complete media, and cells are replated at a density of 5000 cells per well in drug-free complete media. Cells are grown until the DMSO control wells are confluent. Cells are stained with crystal violet dye, washed with distilled water, and imaged using a digital scanner.

Animal Study:

[1]

  • Animal Models

    Nude mice bearing established HCT116 tumors

  • Dosages

    3.75, 7.5, or 15 mg/kg

  • Administration

    Orally administered

Customer Product Validation

, , Am J Transl Res, 2013, 5(3):359-367.

Data from [Data independently produced by , , Neurol Res, 2015, 37(8):703-11]

Selleck's AMG-900 has been cited by 23 publications

DELs enable the development of BRET probes for target engagement studies in cells [ Cell Chem Biol, 2023, 30(8):987-998.e24] PubMed: 37490918
Poziotinib for EGFR exon 20-mutant NSCLC: Clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity [ Cancer Cell, 2022, 40(7):754-767.e6] PubMed: 35820397
Primary Cilia Restrain PI3K-AKT Signaling to Orchestrate Human Decidualization [ Int J Mol Sci, 2022, 23(24)15573] PubMed: 36555215
Primary Cilia Restrain PI3K-AKT Signaling to Orchestrate Human Decidualization [ Int J Mol Sci, 2022, 23(24)15573] PubMed: 36555215
TubulinTracker, a Novel In Vitro Reporter Assay to Study Intracellular Microtubule Dynamics, Cell Cycle Progression, and Aneugenicity [ Toxicol Sci, 2022, kfac008] PubMed: 35094094
In vitro human cell-based aneugen molecular mechanism assay [ Environ Mol Mutagen, 2022, 63(3):151-161] PubMed: 35426156
Cyclin-dependent Kinase 1 and Aurora Kinase choreograph mitotic storage and redistribution of a growth factor receptor [ PLoS Biol, 2021, 19(1):e3001029] PubMed: 33395410
Inhibition of Aurora kinase A activity enhances the antitumor response of beta-catenin blockade in human adrenocortical cancer cells [ Mol Cell Endocrinol, 2021, 528:111243] PubMed: 33716050
Experiments in the EpiDerm™ 3D Skin in Vitro Model and Minipigs in Vivo Indicate Comparatively Lower in Vivo Skin Sensitivity of Topically Applied Aneugenic Compounds [ Toxicol Sci, 2021, kfaa189] PubMed: 33481035
Biomarkers of DNA Damage Response Improves In Vitro Micronucleus Assays by Revealing Genotoxic Mode of Action and Reducing the Occurrence of Irrelevant Positive Results [ Mutagenesis, 2021, geab039] PubMed: 34718711

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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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