The Development of CK2 Inhibitors: From Traditional Pharmacology to in Silico Rational Drug Design

Abstract

Casein kinase II (CK2) is an ubiquitous and pleiotropic serine/threonine protein kinase able to phosphorylate hundreds of substrates. Being implicated in several human diseases, from neurodegeneration to cancer, the biological roles of CK2 have been intensively studied. Upregulation of CK2 has been shown to be critical to tumor progression, making this kinase an attractive target for cancer therapy. Several CK2 inhibitors have been developed so far, the first being discovered by “trial and error testing”. In the last decade, the development of in silico rational drug design has prompted the discovery, de novo design and optimization of several CK2 inhibitors, active in the low nanomolar range. The screening of big chemical libraries and the optimization of hit compounds by Structure Based Drug Design (SBDD) provide telling examples of a fruitful application of rational drug design to the development of CK2 inhibitors. Ligand Based Drug Design (LBDD) models have been also applied to CK2 drug discovery, however they were mainly focused on methodology improvements rather than being critical for de novo design and optimization. This manuscript provides detailed description of in silico methodologies whose applications to the design and development of CK2 inhibitors proved successful and promising.

Hit identification of CK2 inhibitors by virtual screening

“…Almost all CK2 inhibitors block the ATPacceptor site. Benzoimidazoles, anthraquinones, flavonoids, coumarins, and pyrazolotriazines are the most represented families of CK2 inhibitors [16]. Nowadays, only one of them -CX-4945 passed the second stage of clinical trials [17].…”

Novel small molecule protein kinase CK2 inhibitors exert potent antitumor effects on T98G and SEGA cells in vitro

“…The role of CK2 in many pathologies is well known [9,10]. In particular, it is implicated in cardiovascular pathology, cerebral hypoxia, and neurodegeneration, including Alzheimer's disease [8]. CK2 also contributes to the development of tumour, neoplastic cell proliferation and suppression of apoptosis, and it is overexpressed in various types of cancers, including human glioblastoma [7,13,14,33].…”

Matrix metalloproteinase9 as the protein target in anti-breast cancer drug discovery: an approach by targeting hemopexin domain

“…The advances of computer technology, complemented with robust data from bioinformatics and chemo-informatics, are extremely helpful in doing tasks involving drug design and discovery in respect to reducing the cost and increasing the speed of the investigation [89]. There are several software available that facilitate structure-based drug design (when the crystal structure of the protein is available) [90] and ligand-based drug design (when only the ligand with its biological activity is available) [91]. The software could be free, e.g.…”