AMG900

AMG900 is an orally available, small molecule, ATP-competitive, low single-digit nM, pan-Aurora-kinase inhibitor (AKI). It shows at least 10-fold in vitro selectivity compared with relevant Janus kinase family members, and among other targets including MET, p38, and TIE2. It has shown activity in more than three dozen cell lines, shows time-dependent activity, and is effective in cell lines resistant to antimitotics such as paclitaxel and to other AKIs, alone or with microtubule-targeting agents. Combination therapy with HDAC inhibitors and low doses of AMG900 shows promise. Histone H3 phosphorylation is a useful biomarker.

AMG900 is a potent pan Aurora inhibitor that is active in tumor cell lines irrespective of P-gp or BCRP status. Compound is orally bioavailable in mice, rats, dogs and monkeys.

AMG900 is a potent ATP-competitive inhibitor of Aurora kinases. It exhibits low nanomolar affinity for Aurora kinases (A, B, and C); it also has low nanomolar affinity for DDR1, 10-100 nanomolar affinity for DDR2, LTK, FES, and TIE, and 100-200 nanomolar affinity for 5 additional kinases. It is cell permeable (with low nanomolar potency) and orally bioavailable. AMG900 inhibits Aurora kinase autophosphorylation in cells and the phosphorylation of the Aurora kinase substrate histone H3 in a dose-dependent manner. It inhibits the proliferation of 26 tumor cell lines, including cell lines that are resistant to paclitaxel and other Aurora kinase inhibitors. For the purpose of interrogating Aurora kinase function specifically, it might be important to test alongside other Aurora kinases inhibitors with different off-target profiles.