A Selective Biligand Inhibitor of CK2 Increases Caspase-3 Activity in Cancer Cells and Inhibits Platelet Aggregation.

Abstract:

:Cancer cells express high levels of CK2, and its inhibition leads to apoptosis. CK2 has therefore emerged as a new drug target for cancer therapy. A biligand inhibitor ARC-772 was constructed by conjugating 4-(2-amino-1,3-thiazol-5-yl)benzoic acid and a carboxylate-rich peptoid. ARC-772 was found to bind CK2 with a Kd value of 0.3 nm and showed remarkable CK2 inhibitory selectivity in a panel of 140 protein kinases (Gini coefficient: 0.75 at c=100 nm). ARC-775, the acetoxymethyl ester prodrug of ARC-772, was efficiently taken up by cells. Once internalized, the inhibitor is activated by cellular esterase activity. In HeLa cancer cells ARC-775 was found to activate caspase-3 (an apoptosis marker) at sub-micromolar concentrations (EC50 =0.3 μm), a 20-fold lower extracellular concentration than CX-4945, the only CK2 inhibitor under clinical trials. At micromolar concentrations, ARC-775 was also found to inhibit ADP-induced aggregation of human platelets. The overall results of this study demonstrate that oligo-anionic biligand inhibitors have good potential for drug development.

journal_name

ChemMedChem

journal_title

ChemMedChem

authors

Rahnel H,Viht K,Lavogina D,Mazina O,Haljasorg T,Enkvist E,Uri A

doi

10.1002/cmdc.201700457

subject

Has Abstract

pub_date

2017-10-20 00:00:00

pages

1723-1736

issue

20

eissn

1860-7179

issn

1860-7187

journal_volume

12

pub_type

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