AMG 900 (AMG-900), a phtha-lazinamine compound, is a novel and ATP-competitive pan-Aurora (A/B/C) kinase inhibitor with potential antitumor activity. It inhibits Aurora A/B/C with IC50s of 5 nM, 4 nM, and 1 nM, respectively. It is >10-fold more selective for Aurora kinases than p38α, Tyk2, JNK2, Met and Tie2. AMG900 shows potent in vitro antiproliferative activity against 26 different tumor cell lines.

Physicochemical Properties

Molecular Formula	C28H21N7OS
Molecular Weight	503.58
Exact Mass	503.152
CAS #	945595-80-2
Related CAS #	945595-80-2
PubChem CID	24856041
Appearance	Light yellow to yellow solid powder
Density	1.4±0.1 g/cm3
Boiling Point	778.7±70.0 °C at 760 mmHg
Flash Point	424.7±35.7 °C
Vapour Pressure	0.0±2.7 mmHg at 25°C
Index of Refraction	1.739
LogP	4.64
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	9
Rotatable Bond Count	6
Heavy Atom Count	37
Complexity	725
Defined Atom Stereocenter Count	0
InChi Key	IVUGFMLRJOCGAS-UHFFFAOYSA-N
InChi Code	InChI=1S/C28H21N7OS/c1-17-15-24(37-16-17)25-20-5-2-3-6-21(20)26(35-34-25)32-18-8-10-19(11-9-18)36-27-22(7-4-13-30-27)23-12-14-31-28(29)33-23/h2-16H,1H3,(H,32,35)(H2,29,31,33)
Chemical Name	N-(4-((3-(2-aminopyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-4-(4-methylthiophen-2-yl)phthalazin-1-amine.
Synonyms	AMG-900; AMG 900; AMG900
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

ln Vitro	AMG 900 suppresses the enzymatic activity of all three Aurora kinase family members at IC50 levels of 5 nM or lower. In HeLa cells, AMG 900 suppresses autophosphorylation of aurora-A and -B in a concentration-dependent manner. After 48 hours of treatment with 50 nM AMG 900, HCT116 cells were polyploid and colony formation was suppressed. AMG 900 suppresses cell growth, with EC50 values ranging from 0.7 to 5.3 nM. Importantly, four of the AMG 900-sensitive cell lines (HCT-15, MES-SA-Dx5, 769P, and SNU449) were resistant to paclitaxel and other anticancer drugs. AMG 900 inhibits p-histone H3 or causes polyploidy in all cell lines evaluated with consistent potency (IC50 or EC50 values ranging from 2 to 3 nM), regardless of P-gp or BCRP status [1].
ln Vivo	In all nine xenograft models evaluated, AMG 900 showed considerable antitumor efficacy (TGI 50%-97%, P<0.005, P<0.0005 compared to vehicle-treated controls). It is noteworthy that AMG 900 demonstrated activity in xenograft models MES-SA-Dx5 (84% TGI, P<0.0001) and NCI-H460-PTX (66% TGI, P<0.0001) that reacted to docetaxel or paclitaxel resistance when given at the corresponding maximum tolerated dose. AMG 900 decreases the growth of various xenografts representing distinct tumor types and suppresses aurora-B activity in HCT116 tumors [1]. When compared to vehicle-treated controls, treatment with 15 mg/kg AMG 900 effectively suppressed p-histone H3 in the G2M cell population in mouse bone marrow and cytokeratin-positive COLO 205 tumors [2]. AMG 900 has a small volume of dispersion and low to moderate clearance. Its half-life for terminal elimination ranges from 0.6 to 2.4 hours. In animals that have fasted, AMG 900 is well absorbed; its oral bioavailability ranges from 31% to 107%. The amount of food consumed influences how quickly (rats) or deeply (dogs) AMG 900 is absorbed orally [3].
Animal Protocol	Dissolved in DMSO; 3.75, 7.5, or 15 mg/kg; Oral gavage Nude mice bearing established HCT116 tumors
References	[1]. Preclinical evaluation of AMG 900, a novel potent and highly selective pan-aurora kinase inhibitor with activity in taxane-resistant tumor cell lines. Cancer Res, 2010, 70(23), 9846-9854. [2]. AMG 900, a potent inhibitor of aurora kinases causes pharmacodynamic changes in p-Histone H3 immunoreactivity in human tumor xenografts and proliferating mouse tissues. J Transl Med. 2014 Nov 4;12:307. [3]. In vitro and in vivo pharmacokinetic characterizations of AMG 900, an orally bioavailable small molecule inhibitor of aurora kinases. Xenobiotica. 2011 May;41(5):400-8.
Additional Infomation	Aurora Kinase Inhibitor AMG 900 is a small-molecule inhibitor of Aurora kinases A, B and C with potential antineoplastic activity. Aurora kinase inhibitor AMG 900 selectively binds to and inhibits the activities of Aurora kinases A, B and C, which may result in inhibition of cellular division and proliferation in tumor cells that overexpress these kinases. Aurora kinases are serine-threonine kinases that play essential roles in mitotic checkpoint control during mitosis and are overexpressed by a wide variety of cancer cell types.

Solubility Data

Solubility (In Vitro)

DMSO: 100 mg/mL (198.6 mM) Water:<1 mg/mL Ethanol:<1 mg/mL

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 5 mg/mL (9.93 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 5 mg/mL (9.93 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: 1% DMSO+30% polyethylene glycol+1% Tween 80: ~20mg/mL  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	1.9858 mL	9.9289 mL	19.8578 mL
	5 mM	0.3972 mL	1.9858 mL	3.9716 mL
	10 mM	0.1986 mL	0.9929 mL	1.9858 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.