Identification and Biological Evaluation of CK2 Allosteric Fragments through Structure-Based Virtual Screening.

Chunqiong Li,Lijiao Zhao,Yue Zhou,Rugang Zhong,Na Zhang,Guohui Sun,Xuewen Zhang

doi:10.3390/molecules25010237

Abstract

Casein kinase II (CK2) is considered as an attractive cancer therapeutic target, and recent efforts have been made to develop its ATP-competitive inhibitors. However, achieving selectivity with respect to related kinases remains challenging due to the highly conserved ATP-binding pocket of kinases. Allosteric inhibitors, by targeting the much more diversified allosteric site relative to the highly conserved ATP-binding pocket, might be a promising strategy with the enhanced selectivity and reduced toxicity than ATP-competitive inhibitors. The previous studies have highlighted the traditional serendipitousity of discovering allosteric inhibitors owing to the complicate allosteric modulation. In this current study, we identified the novel allosteric inhibitors of CK2α by combing structure-based virtual screening and biological evaluation methods. The structure-based pharmacophore model was built based on the crystal structure of CK2α-compound 15 complex. The ChemBridge fragment library was searched by evaluating the fit values of these molecules with the optimized pharmacophore model, as well as the binding affinity of the CK2α-ligand complexes predicted by Alloscore web server. Six hits forming the holistic interaction mechanism with the αD pocket were retained after pharmacophore- and Alloscore-based screening for biological test. Compound 3 was found to be the most potent non-ATP competitive CK2α inhibitor (IC50 = 13.0 μM) with the anti-proliferative activity on A549 cancer cells (IC50 = 23.1 μM). Our results provide new clues for further development of CK2 allosteric inhibitors as anti-cancer hits.

Highlights

Protein kinase CK2 is involved in multiple physiological processes by phosphorylation of many substrates as the cell survival promoter and apoptosis suppressor [1,2,3]
We aimed to explore the discovery of novel allosteric inhibitors targeting the αD pocket of CK2α using structure-based virtual screening method
The structure-based pharmacophore model with 18 features was built based on the crystal structure of CK2α in complexed with compound 15

Summary

Introduction

Protein kinase CK2 is involved in multiple physiological processes by phosphorylation of many substrates as the cell survival promoter and apoptosis suppressor [1,2,3]. This kinase is considered to be the promising cancer therapeutic target, and many efforts have been made on the discovery of CK2 inhibitors for the cancer therapy. The conventional strategy for CK2 inhibition focused on the discovery of orthosteric molecules that bind into the conserved ATP-binding site [4,5,6]. The allosteric inhibitors targeting the sites out of the catalytic pocket are becoming an alternative strategy. Identification of allosteric pockets is the basis for the design of allosteric inhibitors

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Results

Conclusion