title: Potent and Selective CK2 Kinase Inhibitors with Effects on Wnt Pathway Signaling in Vivo.
abstract: The Wnt pathway is an evolutionarily conserved and tightly regulated signaling network with important roles in embryonic development and adult tissue regeneration. Impaired Wnt pathway regulation, arising from mutations in Wnt signaling components, such as Axin, APC, and β-catenin, results in uncontrolled cell growth and triggers oncogenesis. To explore the reported link between CK2 kinase activity and Wnt pathway signaling, we sought to identify a potent, selective inhibitor of CK2 suitable for proof of concept studies in vivo. Starting from a pyrazolo[1,5-a]pyrimidine lead (2), we identified compound 7h, a potent CK2 inhibitor with picomolar affinity that is highly selectivity against other kinase family enzymes and inhibits Wnt pathway signaling (IC50 = 50 nM) in DLD-1 cells. In addition, compound 7h has physicochemical properties that are suitable for formulation as an intravenous solution, has demonstrated good pharmacokinetics in preclinical species, and exhibits a high level of activity as a monotherapy in HCT-116 and SW-620 xenografts.
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: James E
authors.initials: JE
authors.lastname: Dowling
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Marat
authors.initials: M
authors.lastname: Alimzhanov
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Larry
authors.initials: L
authors.lastname: Bao
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Claudio
authors.initials: C
authors.lastname: Chuaqui
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Denz
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Emma
authors.initials: E
authors.lastname: Jenkins
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Larsen
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Lyne
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Timothy
authors.initials: T
authors.lastname: Pontz
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ye
authors.affiliation: Structure & Biophysics, Discovery Sciences, AstraZeneca R&D , Darwin Building, 310 Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, U.K.
authors.forename: Geoff A
authors.initials: GA
authors.lastname: Holdgate
authors.affiliation: Structure & Biophysics, Discovery Sciences, AstraZeneca R&D , Darwin Building, 310 Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, U.K.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Snow
authors.affiliation: Structure & Biophysics, Discovery Sciences, AstraZeneca R&D , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Nichole
authors.initials: N
authors.lastname: O'Connell
authors.affiliation: Structure & Biophysics, Discovery Sciences, AstraZeneca R&D , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Ferguson
keywords: CK2 kinase; Wnt; pyrazolo[1,5-a]pyrimidine; β-catenin