Discovery of a Potent, Injectable Inhibitor of Aurora Kinases Based on the Imidazo-[1,2-a]-Pyrazine Core
ACS Medicinal Chemistry Letters2010Vol. 1(5), pp. 214–218
Citations Over TimeTop 21% of 2010 papers
Tao Yu, Jayaram R. Tagat, Angela D. Kerekes, Ronald J. Doll, Yonglian Zhang, Yushi Xiao, Sara Esposite, David Belanger, Patrick J. Curran, Amit Kumar Mandal, M. Arshad Siddiqui, Neng‐Yang Shih, Andrea Basso, Ming Liu, Kimberly Gray, Seema Tevar, J. Shawn Jones, Suining Lee, Lianzhu Liang, Samad Ponery, Elizabeth B. Smith, Alan Hruza, Johannes Voigt, Lata Ramanathan, W.W. Prosise, Mengwei Hu
Abstract
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 μM). 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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