AMG-900

ArtNr	S2719-5
Hersteller	Selleckchem
CAS-Nr.	945595-80-2
Menge	5 mg
Quantity options	10 mg 1 g 10 g 10 mM/1 mL 200 mg 5 mg 50 mg 5 g
Kategorie	Oncology Neuroscience Neural Signaling Inhibitors & Compound Libraries Small Molecules By Organ Heart & Blood Cancer
Typ	Inhibitors
Specific against	other
Smiles	CC1=CSC(=C1)C2=NN=C(C3=CC=CC=C32)NC4=CC=C(C=C4)OC5=C(C=CC=N5)C6=NC(=NC=C6)N
ECLASS 10.1	32160490
ECLASS 11.0	32160490
UNSPSC	12000000
Alias	Aurora A,Aurora B,Aurora C,p38alpha,Aurora Kinase
Similar products	AMG
Lieferbar
Storage Conditions	2 years -80 in solvent
Molecular Weight	503, 58
Administration	Orally administered
Animal Models	Nude mice bearing established HCT116 tumors
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.
Clinical Trials	AMG 900 is now under two Phase 1 clinical trials, one is for the orally administration in adult subjects with acute leukemias and related disorders, the other is for evaluating the safety, tolerability and PK in advanced solid tumors.
Concentrations	0.5, 5.0, 50 nM
Dosages	3.75, 7.5, or 15 mg/kg
Formulation	AM 900 is dissolved in DMSO.
IC50	5 nM, 5 nM, 5 nM, 5 nM, 5 nM, 5 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 to the antimitotic drug paclitaxel 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]
Incubation Time	48 hours
Kinase Assay	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, p38alpha, TYK2, JNK2, JAK3, c-Met, VEGFR2, p38beta, TIE-2, ABL (T315I), ERK1, BTK, JNK3, CDK5, PKAalpha, JNK1, p70S6K, PKBalpha, 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).
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.
Solubility (25C)	DMSO 100 mg/mL, Water <1 mg/mL, Ethanol <1 mg/mL
Information	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.
Chemical Name	N-(4-(3-(2-aminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(4-methylthiophen-2-yl)phthalazin-1-amine

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