Abstract
The Aurora kinase family comprises of cell cycle-regulated serine/threonine kinases important for mitosis. Their activity and protein expression are cell cycle regulated, peaking during mitosis to orchestrate important mitotic processes including centrosome maturation, chromosome alignment, chromosome segregation, and cytokinesis. In humans, the Aurora kinase family consists of three members; Aurora-A, Aurora-B, and Aurora-C, which each share a conserved C-terminal catalytic domain but differ in their sub-cellular localization, substrate specificity, and function during mitosis. In addition, Aurora-A and Aurora-B have been found to be overexpressed in a wide variety of human tumors. These observations led to a number of programs among academic and pharmaceutical organizations to discovering small molecule Aurora kinase inhibitors as anti-cancer drugs. This review will summarize the known Aurora kinase inhibitors currently in the clinic, and discuss the current and future directions.
Highlights
The Aurora kinases are a family of highly conserved serine/threonine kinases that are important for faithful transition through mitosis [1,2,3]
A great effort has been focused on investigating different approaches to enhance the effect of Aurora kinase inhibitors in preclinical models and in clinical trials, including investigating the role of Aurora-A in DNA-damage response (DDR)
Aurora-A expression inhibits RAD51 recruitment to DNA DSBs, decreases DSB repair by homologous recombination (HR) and sensitizes cancer cells to PARP inhibition [89]. This impairment of RAD51 function requires inhibition of CHK1 by PLK1. These results identify a novel function of Aurora-A in modulating the response to DNA DSB that likely contributes to carcinogenesis and suggest a novel therapeutic approach to the treatment of cancers overexpressing this protein
Summary
The Aurora kinases are a family of highly conserved serine/threonine kinases that are important for faithful transition through mitosis [1,2,3]. In these Phase I and II studies, danusertib was generally well tolerated, neutropenia being one of the most commonly observed hematologic toxicities, but showed only marginal antitumor activity in patients with common advanced solid tumors who had failed systemic therapy [52]. Danusertib has shown an acceptable toxicity profile and promising activity in patients with advanced hematologic malignancies resistant to imatinib and/or other second generation ABL kinase inhibitors [56].
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