945595-80-2

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 (Item No. 10461) 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.

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 taxane- resistant tumor cell lines.

Aurora A

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.