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

  • ACS Med Chem Lett. 2010 Jun 7;1(5):214-8. doi: 10.1021/ml100063w.
Tao Yu  1 ,  Jayaram R Tagat  1 ,  Angela D Kerekes  1 ,  Ronald J Doll  1 ,  Yonglian Zhang  1 ,  Yushi Xiao  1 ,  Sara Esposite  1 ,  David B Belanger  2 ,  Patrick J Curran  2 ,  Amit K Mandal  2 ,  M Arshad Siddiqui  2 ,  Neng-Yang Shih  2 ,  Andrea D Basso  3 ,  Ming Liu  3 ,  Kimberly Gray  3 ,  Seema Tevar  3 ,  Jennifer Jones  3 ,  Suining Lee  3 ,  Lianzhu Liang  3 ,  Samad Ponery  3 ,  Elizabeth B Smith  3 ,  Alan Hruza  4 ,  Johannes Voigt  4 ,  Lata Ramanathan  4 ,  Winifred Prosise  4 ,  Mengwei Hu  5
Affiliations
  • 1. Departments of Chemical Research.
  • 2. Department of Chemical Research.
  • 3. Oncology.
  • 4. Structural Chemistry.
  • 5. Pharmaceutical Sciences.
PMID: 24900197 DOI: 10.1021/ml100063w
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.

Keywords
Aurora kinase inhibitors; SCH 1473759; aqueous solubility; cell potency; imidazo-[1,2-a]-pyrazine; tumor xenograft model.
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