Discovery of a Potent, Injectable Inhibitor of Aurora Kinases Based on the Imidazo-[1,2-a]-Pyrazine Core

• Published in: ACS medicinal chemistry letters Vol. 1; no. 5; pp. 214 - 218
• Main Authors: Yu, Tao, Tagat, Jayaram R, Kerekes, Angela D, Doll, Ronald J, Zhang, Yonglian, Xiao, Yushi, Esposite, Sara, Belanger, David B, Curran, Patrick J, Mandal, Amit K, Siddiqui, M. Arshad, Shih, Neng-Yang, Basso, Andrea D, Liu, Ming, Gray, Kimberly, Tevar, Seema, Jones, Jennifer, Lee, Suining, Liang, Lianzhu, Ponery, Samad, Smith, Elizabeth B, Hruza, Alan, Voigt, Johannes, Ramanathan, Lata, Prosise, Winifred, Hu, Mengwei
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 12-08-2010
• Subjects: Letter; SCH 1473759; Aurora kinase inhibitors; cell potency; aqueous solubility; imidazo-[1,2-a]-pyrazine; tumor xenograft model
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/ml100063w

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.