Potent and Selective CK2 Kinase Inhibitors with Effects on Wnt Pathway Signaling in Vivo

详细信息    查看全文

• 作者：James E. Dowling ; Marat Alimzhanov ; Larry Bao ; Claudio Chuaqui ; Christopher R. Denz ; Emma Jenkins ; Nicholas A. Larsen ; Paul D. Lyne ; Timothy Pontz ; Qing Ye ; Geoff A. Holdgate ; Lindsay Snow ; Nichole O’Connell ; Andrew D. Ferguson
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：March 10, 2016
• 年：2016
• 卷：7
• 期：3
• 页码：300-305
• 全文大小：459K
• ISSN：1948-5875

文摘

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.