AMG 900 is a novel potent and highly selective Pan-aurora kinase inhibitor with an IC50 of median 3.5 nM. AMG 900 repressed autophosphorylation of aurorakinases A and B as well as the phosphorylation of histone H3.The predominant cellular response of tumor cells to AMG 900treatment is aborted cell division without a mitotic arrest, which leads to endoreduplication and cell death. AMG 900 suppressed the proliferation of tumor cell lines at low nanomolar concentrations (EC50 values 1–6nM). Importantly, AMG 900 was equally potent against multidrugresistant(MDR) cell lines expressing ATP-binding cassette transporters(P-gp and BCRP1). However, paclitaxel and three aurora kinase inhibitors (AZD1152, MK-0457, and PHA-739358) indicated ed a loss of potency in these MDR-positive cell lines compared with matched parental cell lines. AMG 900 induced an accumulation of cells with 4N DNA content (EC50 value 5 nM) and prevented colony formation in this AZD1152-resistant HCT116 subline. [1] AMG 900 was rapidly metabolized in liver microsomes and highly bound to plasma proteins in the species tested. AMG 900 was a weak Pgp substrate with good passive permeability. [2] AMG 900 was originally developed by Amgen. A phase 1 first-in-human study evaluating AMG 900 in advanced solid tumors is currently recruiting participants. |
