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

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

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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