Unveiling the promise of pyrimidine-modified CDK inhibitors in cancer treatment.

ABSTRACT

Cyclin-dependent kinases (CDKs) constitute a vital family of protein-serine kinases, pivotal in regulating various cellular processes such as the cell cycle, metabolism, proteolysis, and neural functions. Dysregulation or overexpression of CDK kinases is directly linked to the development of cancer. However, the currently approved CDK inhibitors by the US FDA, such as palbociclib, ribociclib, Trilaciclib, Abemaciclib, etc., although effective, exhibit limited specificity and often lead to undesirable adverse effects. First and second-generation CDK inhibitors have not gained significant clinical interaction due to their high toxicity and lack of specificity. To address these challenges, a combined approach is being employed in the quest for newer CDK inhibitors aimed at mitigating toxicity and side effects associated with CDKIs. The discovery of therapeutic agents selectively targeting tumorous cells, such as CDK inhibitors, has demonstrated promise in treating various cancers, including breast cancer. Extensive literature reviews have facilitated the development of novel CDK inhibitors by combining medicinally preferred pyrimidine derivatives with other heterocyclic rings. Pyrimidine derivatives substituted with pyrazole, imidazole, benzamide, benzene sulfonamide, indole carbohydrazide, and other privileged heterocyclic rings have shown encouraging efficacy in inhibiting cyclin-dependent kinase activity. This review provides comprehensive data, including structure-activity relationship (SAR), anticancer activity, and kinetics studies of potent compounds. Additionally, molecular docking studies with compounds under clinical trial and patents filed on pyrimidine based CDK inhibitors in cancer treatment are included. This review serves as a valuable resource for further development of CDK kinase inhibitors for cancer treatment, offering insights into their efficacy, specificity, and potential clinical applications.