Potent and Selective Inhibitors of CK2 Kinase Identified through Structure-Guided Hybridization

Abstract

In this paper we describe a series of 3-cyano-5-aryl-7-aminopyrazolo[1,5-a]pyrimidine hits identified by kinase-focused subset screening as starting points for the structure-based design of conformationally constrained 6-acetamido-indole inhibitors of CK2. The synthesis, SAR, and effects of this novel series on Akt signaling and cell proliferation in vitro are described.

Targeted Regulation of PI3K/Akt/mTOR/NF-κB Signaling by Indole Compounds and their Derivatives: Mechanistic Details and Biological Implications for Cancer Therapy

“…5) [111]. Though developed for targeting CK2 kinase, both compounds also revealed strong inhibition of AKT phosphorylation (IC 50 = 34 nM for 16a , 27 nM for 16b ).…”

Structure and Property Based Design of Pyrazolo[1,5-a]pyrimidine Inhibitors of CK2 Kinase with Activity in Vivo

“…7 We have recently described the design of a series of conformationally constrained inhibitors of CK2 containing the pyrazolo [1,5-a]pyrimidine nucleus. 8 Members of this series of compounds exhibited potent inhibition of the enzyme, possessed a high degree of kinase selectivity, and depleted cellular levels of pAKT S129 , a direct substrate of CK2 believed to hyperactivate the AKT pathway. 9 Although our attempts to enhance both cellular potency and physical properties in this series were unsuccessful, these studies resulted in an understanding of the structure−property relationships within the scaffold and provided additional insights into ligand−receptor binding.…”

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

“…An early probe from our previously described series of ATP-competitive pyrazolo[1,5-a]pyrimidine-derived inhibitors of CK2 (1, 2; Figure 1) was used to assess the link between CK2 inhibition and Wnt signaling. 10 Treatment of DLD-1(APC mutant) cells with 2 inhibits β-catenin phosphorylation and decreases Wnt-mediated gene transcription as shown in a Luciferase reporter assay in APC …”

“…An early probe from our previously described series of ATP-competitive pyrazolo [1,5-a]pyrimidine-derived inhibitors of CK2 (1, 2; Figure 1) was used to assess the link between CK2 inhibition and Wnt signaling. 10 Treatment of DLD-1(APC mutant) cells with 2 inhibits β-catenin phosphorylation and decreases Wnt-mediated gene transcription as shown in a Luciferase reporter assay in APC mutant DLD-1 cells (IC 50 = 0.06 μM). 11 In an acute dose pharmacokinetic/pharmacodynamic (PK/PD) study, treatment of DLD-1/AKT1 overexpressing murine xenografts with 2 (10 mg/kg, PO) resulted in the 20% inhibition of Wnt-mediated luciferase gene transcription at 8 h, and coincided with an unbound drug concentration at the level of the Wnt reporter IC 50 .…”

“…When tested in disease model studies using a murine DLD-1(APC mut ) xenograft, compound 2 showed limited tumor growth inhibition. 10 Our medicinal chemistry strategy subsequently focused on achieving potent inhibition of the Wnt pathway, as demonstrated using a Wnt luciferase reporter assay in DLD-1 cells, 11 while seeking to improve physicochemical properties, enhance target coverage, and potentially deliver increased in vivo efficacy in preclinical models characterized by aberrant Wnt signaling.…”