Pyrimidine scaffold dual-target kinase inhibitors for cancer diseases: A review on design strategies, synthetic approaches, and structure-activity relationship (2018-2023)

Abstract

Cancer, the second leading cause of death globally, causes a significant threat to life. Despite advancements in the treatment of cancer, persistent challenges include severe side effects and the emergence of acquired drug resistance. Additionally, many traditional chemotherapy drugs show restricted efficacy and high toxicity, primarily attributed to their lack of selectivity. Thus, the development of drugs targeting protein kinases has emerged as a noteworthy priority for addressing human cancers. Medicinal chemists have shown considerable interest in the development of dual drug candidates as a strategy to create medicines that are safer, more efficient, and cost-effective. Furthermore, the Food and Drug Administration (FDA) has approved several dual-target drugs for anticancer treatment, emphasizing their lower risks of drug interactions and improved pharmacokinetics and safety profiles. This review focuses on the synthetic efforts, design strategies, and structure-activity relationship of the pyrimidine scaffold-based dual kinase inhibitors developed with anticancer potential within the recent 6 years (2018-2023). Collectively, these strategies are expected to offer fresh perspectives on the future directions of pyrimidine-based dual-target kinase drug design, potentially advancing cancer therapeutics.