title: 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 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.
authors.affiliation: Departments of Chemical Research.
authors.forename: Tao
authors.initials: T
authors.lastname: Yu
authors.affiliation: Departments of Chemical Research.
authors.forename: Jayaram R
authors.initials: JR
authors.lastname: Tagat
authors.affiliation: Departments of Chemical Research.
authors.forename: Angela D
authors.initials: AD
authors.lastname: Kerekes
authors.affiliation: Departments of Chemical Research.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Doll
authors.affiliation: Departments of Chemical Research.
authors.forename: Yonglian
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Departments of Chemical Research.
authors.forename: Yushi
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Departments of Chemical Research.
authors.forename: Sara
authors.initials: S
authors.lastname: Esposite
authors.affiliation: Department of Chemical Research.
authors.forename: David B
authors.initials: DB
authors.lastname: Belanger
authors.affiliation: Department of Chemical Research.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Curran
authors.affiliation: Department of Chemical Research.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Mandal
authors.affiliation: Department of Chemical Research.
authors.forename: M Arshad
authors.initials: MA
authors.lastname: Siddiqui
authors.affiliation: Department of Chemical Research.
authors.forename: Neng-Yang
authors.initials: NY
authors.lastname: Shih
authors.affiliation: Oncology.
authors.forename: Andrea D
authors.initials: AD
authors.lastname: Basso
authors.affiliation: Oncology.
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.affiliation: Oncology.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Gray
authors.affiliation: Oncology.
authors.forename: Seema
authors.initials: S
authors.lastname: Tevar
authors.affiliation: Oncology.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jones
authors.affiliation: Oncology.
authors.forename: Suining
authors.initials: S
authors.lastname: Lee
authors.affiliation: Oncology.
authors.forename: Lianzhu
authors.initials: L
authors.lastname: Liang
authors.affiliation: Oncology.
authors.forename: Samad
authors.initials: S
authors.lastname: Ponery
authors.affiliation: Oncology.
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Smith
authors.affiliation: Structural Chemistry.
authors.forename: Alan
authors.initials: A
authors.lastname: Hruza
authors.affiliation: Structural Chemistry.
authors.forename: Johannes
authors.initials: J
authors.lastname: Voigt
authors.affiliation: Structural Chemistry.
authors.forename: Lata
authors.initials: L
authors.lastname: Ramanathan
authors.affiliation: Structural Chemistry.
authors.forename: Winifred
authors.initials: W
authors.lastname: Prosise
authors.affiliation: Pharmaceutical Sciences.
authors.forename: Mengwei
authors.initials: M
authors.lastname: Hu
keywords: Aurora kinase inhibitors; SCH 1473759; aqueous solubility; cell potency; imidazo-[1,2-a]-pyrazine; tumor xenograft model