Small molecule modulators targeting protein kinase CK1 and CK2

Abstract Casein kinase (CK) is a type of conserved serine/threonine protein kinase that phosphorylates many important proteins in body. Researchers found that CK is involved in a variety of signaling pathways, and also plays an important role in inflammation, cancer, and nervous system diseases. Thus, it is considered to be a promising target for the treatment of related diseases. Many CK small molecule inhibitors have been reported so far, and most are ATP competitive inhibitors. However, these CK inhibitors lack the basic properties required for in vivo use, such as selectivity, cell permeability, metabolic stability, correct pharmacokinetic characteristics, and cellular environment. But small molecule inhibitors still have an advantage in drug research due to their controllable pharmacological and pharmacokinetic properties. CX-4945 discovered by Cylene Pharmaceutical is the only one CK2 inhibitor entering into Phase II clinical trials till now. In recent years, significant advances have been made in the design of non-competitive inhibitors of CK and in the application of multi-target inhibition strategies. Here, we review the published CK inhibitors and analyze their structure-activity relationships (SAR). We also summarized the eutectic structure with identified hot spots to provide a reference for future drug discovery.