Synthetic Strategies of Pyrimidine-Based Scaffolds as Aurora Kinase and Polo-like Kinase Inhibitors.

The past few decades have witnessed significant progress in anticancer drug discovery. Small molecules containing heterocyclic moieties have attracted considerable interest for designing new antitumor agents. Of these, the pyrimidine ring system is found in multitude of drug structures, and being the building unit of DNA and RNA makes it an attractive scaffold for the design and development of anticancer drugs. Currently, 22 pyrimidine-containing entities are approved for clinical use as anticancer drugs by the FDA. An exhaustive literature search indicates several publications and more than 59 patents from the year 2009 onwards on pyrimidine derivatives exhibiting potent antiproliferative activity. These pyrimidine derivatives exert their activity via diverse mechanisms, one of them being inhibition of protein kinases. Aurora kinase (AURK) and polo-like kinase (PLK) are protein kinases involved in the regulation of the cell cycle. Within the numerous pyrimidine-based small molecules developed as anticancer agents, this review focuses on the pyrimidine fused heterocyclic compounds modulating the AURK and PLK proteins in different phases of clinical trials as anticancer agents. This article aims to provide a comprehensive overview of synthetic strategies for the preparation of pyrimidine derivatives and their associated biological activity on AURK/PLK. It will also present an overview of the synthesis of the heterocyclic-2-aminopyrimidine, 4-aminopyrimidine and 2,4-diaminopyrimidine scaffolds, and one of the pharmacophores in AURK/PLK inhibitors is described systematically.

Design strategies, SAR, and mechanistic insight of Aurora kinase inhibitors in cancer.

Aurora kinases (AURKs) are serine/threonine protein kinases that play a critical role during cell proliferation. Three isoforms of AURKs reported in mammals include AURKA, AURKB, AURKC, and all share a similar C-terminal catalytic domain with differences in their subcellular location, substrate specificity, and function. Recent research reports indicate an elevated expression of these kinases in several cancer types highlighting their role as oncogenes in tumorigenesis. Inhibition of AURKs is an attractive strategy to design potent inhibitors modulating this target. The last few years have witnessed immense research in the development of AURK inhibitors with few FDA approvals. The current clinical therapeutic regime in cancer is associated with severe side-effects and emerging resistance to existing drugs. This has been the key driver of research initiatives toward designing more potent drugs that can potentially circumvent the emerging resistance. This review is a comprehensive summary of recent research on AURK inhibitors and presents the development of scaffolds, their synthetic schemes, structure-activity relationships, biological activity, and enzyme inhibition potential. We hope to provide the reader with an array of scaffolds that can be selected for further research work and mechanistic studies in the development of new AURK inhibitors.