Strategies of Targeting CK2 in Drug Discovery: Challenges, Opportunities, and Emerging Prospects

Abstract

CK2 (casein kinase 2) is a serine/threonine protein kinase that is ubiquitous in eukaryotic cells and plays important roles in a variety of cellular functions, including cell growth, apoptosis, circadian rhythms, DNA damage repair, transcription, and translation. CK2 is involved in cancer pathogenesis and the occurrence of many diseases. Therefore, targeting CK2 is a promising therapeutic strategy. Although many CK2specific small-molecule inhibitors have been developed, only CX-4945 has progressed to clinical trials. In recent years, novel CK2 inhibitors have gradually become a research hotspot, which is expected to overcome the limitations of traditional inhibitors. Herein, we summarize the structure, biological functions, and disease relevance of CK2 and emphatically analyze the structure−activity relationship (SAR) and binding modes of small-molecule CK2 inhibitors. We also discuss the latest progress of novel strategies, providing insights into new drugs targeting CK2 for clinical practice.

Comprehensive Insights that Targeting PIM for Cancer Therapy: Prospects and Obstacles

“…Considering that natural compounds have remained an important avenue for drug discovery, the recently published PIM inhibitors based on natural products also warrant attention. For these small molecule inhibitors, particular emphasis has been placed on optimization strategies, structure–activity relationships (SARs), and the potency of inhibiting PIM kinases. − …”

Enhanced inhibitory activity of compounds containing purine scaffolds compared to protein kinase CK2α considering crystalline water

“…Protein kinase CK2 (CK2) is involved in various important cellular functions, including signal transduction and gene expression. [1][2][3][4][5][6] CK2 functions as a hetero-tetrameric holoenzyme comprising two catalytic subunits (CK2α and/or CK2α′) and two identical regulatory subunits (CK2β). 7 CK2 is also known to be associated with the progression of glomerulonephritis [8][9][10] neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, etc.…”

Identification of CK2α’ selective inhibitors by the screening of an allosteric-kinase-inhibitor-like compound library

“…It is not surprising that dysregulation of CK2 contributes to the etiology of multiple human diseases, including cancer, neurodegeneration, and even COVID-19 viral infection [4][5][6]. Therefore, CK2 has been the subject of extensive research for the development of effective and selective inhibitors for the treatment of these diseases, with a special focus on cancer treatment [6,7]. However, despite decades of research since the first CK2 inhibitor was identified in 1990, only silmitasertib (CX-4945) has received FDA approval with limited use in clinical trials for some forms of cancer [8][9][10][11][12].…”

“…Several approaches have been used to develop CK2 inhibitors [7]. These approaches include blocking the substrate channel, disrupting the holoenzyme assembly by interfering with CK2β binding, and targeting putative allosteric sites outside the catalytic box [38][39][40], although the most studied mode of inhibition has been through ATP analogs that compete with ATP to prevent substrate phosphorylation [8,39,[41][42][43].…”