期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 1, 期 5, 页码 214-218出版社
AMER CHEMICAL SOC
DOI: 10.1021/ml100063w
关键词
Aurora kinase inhibitors; cell potency; aqueous solubility; imidazo-[1,2-a]-pyrazine; tumor xenograft model; SCH 1473759
The imidazo-[1,2-a]-pyrazine (1) is a dual inhibitor of Aurora kinases A and B with modest cell potency (IC50 = 250 nM) and low solubility (5 mu M). Lead optimization guided by the binding mode led to the acyclic amino alcohol 12k (SCH 1473759), which is a picomolar inhibitor of Aurora kinases (TdF K-d Aur A = 0.02 nM and Aur B = 0.03 nM) with improved cell potency (phos-HH3 inhibition IC50 = 25 nM) and intrinsic aqueous solubility (11.4 mM). It also demonstrated efficacy and target engagement in human tumor xenograft mouse models.
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