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.

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Cyclin-dependent kinase 5 (CDK5) protein plays an important role not only in the central nervous system but also in the periphery, including immune response, regulation of insulin secretion, and cancer development and progression. Consequently, targeting the CDK5 protein is a potential strategy for the treatment of many diseases, especially cancer and neurodegenerative diseases. To date, numerous pan-CDK inhibitors have entered clinical trials. Nevertheless, limited clinical efficacy and severe adverse effects have prompted the application of new techniques to optimize clinical efficacy and minimize adverse events. In this Perspective, we highlight the protein properties, biofunctions, relevant signaling pathways, and associations with cancer development and proliferation of CDK5, and analyze the clinical status of pan-CDK inhibitors and the preclinical status of CDK5-specific inhibitors. In addition, CDK5-selective inhibitors, protein–protein interaction inhibitors, proteolytic-targeting chimera (PROTAC) degraders, and dual-target CDK5 inhibitors are discussed.