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

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 ?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.

SUBMITTER: Yu T

PROVIDER: S-EPMC4007894 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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

Yu Tao T Tagat Jayaram R JR Kerekes Angela D AD Doll Ronald J RJ Zhang Yonglian Y Xiao Yushi Y Esposite Sara S Belanger David B DB Curran Patrick J PJ Mandal Amit K AK Siddiqui M Arshad MA Shih Neng-Yang NY Basso Andrea D AD Liu Ming M Gray Kimberly K Tevar Seema S Jones Jennifer J Lee Suining S Liang Lianzhu L Ponery Samad S Smith Elizabeth B EB Hruza Alan A Voigt Johannes J Ramanathan Lata L Prosise Winifred W Hu Mengwei M

ACS medicinal chemistry letters 20100607 5

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 ...[more]

PMID: 24900197

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