title: Structure and Property Based Design of Pyrazolo[1,5-a]pyrimidine Inhibitors of CK2 Kinase with Activity in Vivo.
abstract: In this letter, we describe the design, synthesis, and structure-activity relationship of 5-anilinopyrazolo[1,5-a]pyrimidine inhibitors of CK2 kinase. Property-based optimization of early leads using the 7-oxetan-3-yl amino group led to a series of matched molecular pairs with lower lipophilicity, decreased affinity for human plasma proteins, and reduced binding to the hERG ion channel. Agents in this study were shown to modulate pAKT(S129), a direct substrate of CK2, in vitro and in vivo, and exhibited tumor growth inhibition when administered orally in a murine DLD-1 xenograft.
authors.affiliation: AstraZeneca , Oncology Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: James E
authors.initials: JE
authors.lastname: Dowling
authors.affiliation: AstraZeneca , Oncology Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Marat
authors.initials: M
authors.lastname: Alimzhanov
authors.affiliation: AstraZeneca , Oncology Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Larry
authors.initials: L
authors.lastname: Bao
authors.affiliation: AstraZeneca , Oncology Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Block
authors.affiliation: AstraZeneca , Oncology Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Claudio
authors.initials: C
authors.lastname: Chuaqui
authors.affiliation: AstraZeneca , Oncology Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Cooke
authors.affiliation: AstraZeneca , Oncology Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Denz
authors.affiliation: AstraZeneca , Oncology Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Alex
authors.initials: A
authors.lastname: Hird
authors.affiliation: AstraZeneca , Oncology Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Shan
authors.initials: S
authors.lastname: Huang
authors.affiliation: AstraZeneca , Oncology Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Larsen
authors.affiliation: AstraZeneca , Oncology Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Bo
authors.initials: B
authors.lastname: Peng
authors.affiliation: AstraZeneca , Oncology Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Pontz
authors.affiliation: AstraZeneca , Oncology Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Caroline
authors.initials: C
authors.lastname: Rivard-Costa
authors.affiliation: AstraZeneca , Oncology Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Jamal Carlos
authors.initials: JC
authors.lastname: Saeh
authors.affiliation: AstraZeneca , Oncology Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Kumar
authors.initials: K
authors.lastname: Thakur
authors.affiliation: AstraZeneca , Oncology Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ye
authors.affiliation: AstraZeneca , Oncology Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: AstraZeneca , Oncology Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Lyne
keywords: CK2 kinase; matched molecular pair; oxetane; pyrazolo[1,5-a]pyrimidine