Design, synthesis, and evaluation of novel aurora kinase inhibitors for cancer diagnosis and therapy

Abstract

Cancer is the second leading cause of death globally. Advances in cancer diagnosis and therapeutics plays a critical role in global health and a patient’s life. Aurora kinases, as mitotic kinases, regulate multiple mitotic events. Their oncogenic properties have made them attractive targets for cancer diagnosis and therapy for two decades. A variety of AURKA/B selective inhibitors and pan-Aurora inhibitors have been developed. Many of these inhibitors have been proven to have effective antitumor properties in both in vitro studies using cell lines and in vivo studies with murine xenografts. However, no inhibitors have been approved for human use. Discovering novel inhibitors that are highly selective and potent represent the task ahead. Such compounds will also serve to derive a better understanding of the biological functions of Aurora kinases. The aim of this thesis is to study the structural mechanism of subtype selective Aurora kinase inhibitors and develop novel radiotracers and inhibitors targeting Aurora kinases for cancer diagnosis and therapeutics. Chapter 1 summarizes the mitotic functions, oncogenic properties and structural characteristics of Aurora kinases and the progress in Aurora inhibitors development. The Aurora kinase family has three members Aurora kinase A, B and C. They are highly conserved with high sequence and structural similarities but differ in their subcellular locations and amplification characters of different cancer types. Inhibiting Aurora kinase A may have long-term effects which lead to a secondary tumor. Targeting Aurora kinase B with highly selective inhibitors is potentially a less toxic anti-cancer strategy. However, the use of the highly selective Aurora kinase B inhibitor is underdeveloped, and most of them have overlapping activity with Aurora kinase C. Therefore, this thesis focuses on developing subtype selective Aurora B/C inhibitors. [...]