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

• Main Authors: Chunqiong Li, Xuewen Zhang, Na Zhang, Yue Zhou, Guohui Sun, Lijiao Zhao, Rugang Zhong
• Format: Article
• Language: English
• Published: MDPI AG 2020-01-01
• Series: Molecules
• Subjects: protein kinase ck2; allosteric fragments; αd pocket; virtual screening; anti-cancer hits
• Online Access: https://www.mdpi.com/1420-3049/25/1/237

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 CK2&#945; by combing structure-based virtual screening and biological evaluation methods. The structure-based pharmacophore model was built based on the crystal structure of CK2&#945;-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 CK2&#945;-ligand complexes predicted by Alloscore web server. Six hits forming the holistic interaction mechanism with the &#945;D pocket were retained after pharmacophore- and Alloscore-based screening for biological test. Compound <b>3</b> was found to be the most potent non-ATP competitive CK2&#945; inhibitor (IC₅₀ = 13.0 &#956;M) with the anti-proliferative activity on A549 cancer cells (IC₅₀ = 23.1 &#956;M). Our results provide new clues for further development of CK2 allosteric inhibitors as anti-cancer hits.