CMGC Kinases in Health and Cancer

SIMPLE SUMMARY: CMGC kinases, named after the initials of its main kinase families, CDKs, MAPKs, GSKs, and CLKs, play critical roles in many cellular processes. Dysregulation of these kinases has been associated with cancer development and progression, highlighting their significance in cancer biology. The success of certain kinase inhibitors demonstrated the therapeutic potential of targeting CMGC kinases. However, the clinical application of CMGC kinase inhibitors is not without its challenges. Here, we discuss the challenges including resistance; off-target effects; patient stratification, which can be addressed through the development of next-generation inhibitors; combination therapies; and exploiting protein–protein interactions involving CMGC kinases. Understanding these interactions could reveal novel targets and allow for the design of drugs that disrupt these specific interactions, offering another layer of precision in targeting these key players in cancer biology. Through continued research and development, next-generation inhibitors and novel therapeutic strategies could play a pivotal role in improving outcomes for cancer patients. ABSTRACT: CMGC kinases, encompassing cyclin-dependent kinases (CDKs), mitogen-activated protein kinases (MAPKs), glycogen synthase kinases (GSKs), and CDC-like kinases (CLKs), play pivotal roles in cellular signaling pathways, including cell cycle regulation, proliferation, differentiation, apoptosis, and gene expression regulation. The dysregulation and aberrant activation of these kinases have been implicated in cancer development and progression, making them attractive therapeutic targets. In recent years, kinase inhibitors targeting CMGC kinases, such as CDK4/6 inhibitors and BRAF/MEK inhibitors, have demonstrated clinical success in treating specific cancer types. However, challenges remain, including resistance to kinase inhibitors, off-target effects, and the need for better patient stratification. This review provides a comprehensive overview of the importance of CMGC kinases in cancer biology, their involvement in cellular signaling pathways, protein–protein interactions, and the current state of kinase inhibitors targeting these kinases. Furthermore, we discuss the challenges and future perspectives in targeting CMGC kinases for cancer therapy, including potential strategies to overcome resistance, the development of more selective inhibitors, and novel therapeutic approaches, such as targeting protein–protein interactions, exploiting synthetic lethality, and the evolution of omics in the study of the human kinome. As our understanding of the molecular mechanisms and protein–protein interactions involving CMGC kinases expands, so too will the opportunities for the development of more selective and effective therapeutic strategies for cancer treatment.