Three Aurora kinases, A-C, are involved in phosphorylation events that are critical for the completion of mitosis. Their expression is elevated in a variety of human cancers. AMG 900 is an orally bioavailable, selective Aurora kinase inhibitor with IC50 values of 5, 4, and 1 nM for Aurora A, B, and C, respectively. It is greater than 10-fold selective for Aurora kinases over p38α, TYK2, JNK2, Met, and Tie2 (IC50s = 53, 220, 520, 550, and 650 nM, respectively). At 2-3 nM, AMG 900 has been shown to inhibit the proliferation of 26 different tumor cell lines in vitro, including cell lines resistant to either the antimitotic agent paclitaxel or to other Aurora kinase inhibitors. Furthermore, AMG 900 is reported to be broadly active in multiple xenograft models, including three multidrug-resistant xenograft models, representing five tumor types.
AMG 900 is a potent and highly selective pan-Aurora kinases inhibitor with IC50 of 5 nM, 4 nM and 1 nM for Aurora A, B and C, respectively.
This potent and highly selective mitotic protein kinase inhibitor (FW = 503.58 g/mol; CAS 945595-80-2; Solubility: 100 mg/mL DMSO), also named N-(4-(3-(2-aminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(4- methylthiophen-2-yl)phthalazin-1-amine, targets Aurora A (IC50 = 5 nM), Aurora B (IC50 = 4 nM), and Aurora C (IC50 = 1 nM) protein kinases, with >10-fold selectivity versus p38α, Tyk2, JNK2, Met and Tie2. The modal tumor cell response to AMG 900 treatment is aborted cell division without prolonged mitotic arrest, ultimately resulting in cell death. AMG 900 exhibits acceptable PK properties in preclinical species and is predicted to have low clearance in humans. Male rats metabolize AMG 900 primarily through hydroxylation with subsequent sulfate conjugation on the pyrimidinyl-pyridine side-chain, whereas female rats favor oxidation on the thiophene ring's methyl group, which is then metabolized to a carboxylic acid, attended by conjugation to an acyl glucuronide. At low-nM concentrations, AMG 900, whether administered alone or in combination with microtubule-targeting drugs (paclitaxel or ixabepilone), may be an effective intervention strategy for the treatment of metastatic breast cancer and provide potential therapeutic options for patients with multidrug-resistant tumors. It is, in fact, also active against taxaneresistant tumor cell lines.
AMG 900 exhibits significant antitumor activity in all 9 xenograft models tested (50%-97% TGI compared with the vehicle-treated control group, P<0.005, P<0.0005). Importantly, AMG 900 is active in the MES-SA-Dx5 (84% TGI, P<0.0001) and NCI-H460-PTX (66% TGI, P<0.0001) xenograft models that are resistant to either Docetaxel or Paclitaxel administered at their respective maximum tolerated doses. AMG 900 inhibits the activity of aurora-B in HCT116 tumors and suppresses the growth of multiple xenografts that represent diverse tumor types[1]. Treatment with AMG 900 at 15 mg/kg significantly inhibits p-Histone H3 in the G2M cell population in mouse bone marrow and cytokeratin positive COLO 205 tumor compared with vehicle-treated controls[2]. 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 h. AMG 900 is well-absorbed in fasted animals with an oral bioavailability of 31% to 107%. Food intake had an effect on rate (rats) or extent (dogs) of AMG 900 oral absorption[3].
Aurora A: 5 nM (IC50); Aurora B: 4 nM (IC50); Aurora C: 1 nM (IC50)
1. payton, m., et al., 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): p. 9846-54.2. geuns-meyer, s., et al., discovery of n-(4-(3-(2-aminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4- (4-methylthiophen-2-yl)p hthalazin-1-amine (amg 900), a highly selective, orally bioavailable inhibitor of aurora kinases with activity against multidrug-resistant cancer cell lines. j med chem, 2015. 58(13): p. 5189-207.
