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Synonyms | N/A | Storage (From the date of receipt) |
3 years -20°C powder 1 years -80°C in solvent |
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化学式 | C28H21N7OS |
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分子量 | 503.58 | CAS No. | 945595-80-2 | |
Solubility (25°C)* | 体外 | 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. |
製品説明 | 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. |
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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] |
キナーゼアッセイ | Enzyme kinase assays | |
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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). | ||
細胞アッセイ | 細胞株 | Different tumor cell lines including NCI-H460, MDA-MB231, MES-SA, NCI-H460 PTX, MDA-MB-231 PTX, MES-SA Dx5, and HCT-15. |
濃度 | 0.5, 5.0, 50 nM | |
反応時間 | 48 hours | |
実験の流れ | 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. |
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動物実験 | 動物モデル | Nude mice bearing established HCT116 tumors |
投薬量 | 3.75, 7.5, or 15 mg/kg | |
投与方法 | Orally administered |
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, , Am J Transl Res, 2013, 5(3):359-367.
Data from [Data independently produced by , , Neurol Res, 2015, 37(8):703-11]
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 |
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 |
Prolonged unfolded protein reaction is involved in the induction of chronic myeloid leukemia cell death upon oprozomib treatment [ Cancer Sci, 2020, 112(1):133-143] | PubMed: 33067904 |
長期の保管のために-20°Cの下で製品を保ってください。
人間や獣医の診断であるか治療的な使用のためにでない。
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