AMG-900 945595-80-2

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Molecular Weight:

503.58 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.


Biological Activity


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).


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. 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.






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


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.

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Product Categories : Epigenetics > Aurora Kinase Inhibitor