Aurora kinases as targets for cancer therapy (original) (raw)
Related papers
Aurora Kinases and Potential Medical Applications of Aurora Kinase Inhibitors: A Review
Journal of Clinical Medicine Research, 2015
Aurora kinases (AKs) represent a novel group of serine/threonine kinases. They were originally described in 1995 by David Glover in the course of studies of mutant alleles characterized with unusual spindle pole configuration in Drosophila melanogaster. Thus far, three AKs A, B, and C have been discovered in human healthy and neoplastic cells. Each one locates in different subcellular locations and they are all nuclear proteins. AKs are playing an essential role in mitotic events such as monitoring of the mitotic checkpoint, creation of bipolar mitotic spindle and alignment of centrosomes on it, also regulating centrosome separation, bio-orientation of chromosomes and cytokinesis. Any inactivation of them can have catastrophic consequences on mitotic events of spindle formation, alignment of centrosomes and cytokinesis, resulting in apoptosis. Overexpression of AKs has been detected in diverse solid and hematological cancers and has been linked with a dismal prognosis. After discovery and identification of the first aurora kinase inhibitor (AKI) ZM447439 as a potential drug for targeted therapy in cancer treatment, approximately 30 AKIs have been introduced in cancer treatment.
Update on aurora kinase targeted therapeutics in oncology
Expert Opinion on Drug Discovery, 2011
Introduction-Mammalian cells contain three distinct serine/threonine protein kinases with highly conserved catalytic domains, including aurora A and B kinases that are essential regulators of mitotic entry and progression. Overexpression of aurora A and/or B kinase is associated with high proliferation rates and poor prognosis, making them ideal targets for anti-cancer therapy. Disruption of mitotic machinery is a proven anti-cancer strategy employed by multiple chemotherapeutic agents. Numerous small molecule inhibitors of the aurora kinases have been discovered and tested in vivo and in vitro, with a few currently in phase II testing.
Targeting Aurora-2 kinase in cancer
Molecular cancer therapeutics, 2003
Aurora-2 kinase has been shown to contribute to oncogenic transformation and is frequently overexpressed and amplified in many human tumor types. Aurora-2 belongs to a small family of mitotic serine/threonine kinases that regulate centrosome maturation, chromosome segregation, and cytokinesis. The mechanism behind the transforming activity of aurora-2 is not fully understood; however, the role of aurora-2 in regulating the centrosome cycle is likely responsible for its ability to transform cells. Aurora-2 overexpression has been correlated with centrosome amplification, which can be a driving cause of genomic instability in tumor cells. In addition, recent work has demonstrated that aurora-2 plays an active function in promoting entry into mitosis by regulating local translation of centrosomal stored mRNA, such as cyclin B1. These recent findings implicate aurora-2 as an important regulator of both genomic integrity and cell cycle progression in cancer cells and suggest that aurora-...
Aurora kinase inhibitors: Progress towards the clinic
Investigational New Drugs, 2012
The Aurora kinases (serine/threonine kinases) were discovered in 1995 during studies of mutant alleles associated with abnormal spindle pole formation in Drosophila melanogaster. They soon became the focus of much attention because of their importance in human biology and association with cancer. Aurora kinases are essential for cell division and are primarily active during mitosis. Following their identification as potential targets for cancer chemotherapy, many Aurora kinase inhibitors have been discovered, and are currently under development. The binding modes of Aurora kinase inhibitors to Aurora kinases share specific hydrogen bonds between the inhibitor core and the back bone of the kinase hinge region, while others parts of the molecules may point to different parts of the active site via noncovalent interactions. Currently there are about 30 Aurora kinase inhibitors in different stages of preclinical and clinical development. This review summarizes the characteristics and status of Aurora kinase inhibitors in preclinical, Phase I, and Phase II clinical studies, with particular emphasis on the mechanisms of action and resistance to these promising anticancer agents. We also discuss the validity of Aurora kinases as oncology targets, on/off-target toxicities, and other important aspects of overall clinical performance and future of Aurora kinase inhibitors.
DRUG DESIGN EFFORTS TOWARD AURORA KINASE INHIBITORS (REVIEW)
In the recent years Aurora kinases have attracted increasing attention as serine serine/threonine kinases with various roles in cell division, including chromosomal agglutination and segration functions of centromeres, centrosomal maturation, spindle formation and cytokinesis. Aurora kinases are overexpressed in a number of cancers and recent studies have shown that they are involved in oncogenesis overexpressed aurora kinases are recently studied and have shown their involvement in oncogenesis and aberrant increase in centrosome number emergence of polykaryocytes and failures of cancer inhibition mechanisms. Several aurora kinase inhibitions have been studied in vitro and in vivo. A number of new aurora kinase inhibitors are being development of numerous aurora kinase inhibitors is likely to increase the number of selectable drugs during treatment. This review showed that different methodology toward the development of aurora kinase inhibitors. KEYWORDS: Serine/threonine, spindle defects, INCENP and virtual screening.
In the recent years Aurora kinases have attracted increasing attention as serine/threonine kinases with various roles in cell division, including chromosomal agglutination and segration functions of centromeres, centrosomal maturation, spindle formation and cytokinesis. Overexpressed aurora kinases are recently studied and have shown their involvement in oncogenesis and aberrant increase in centrosome number emergence of polykaryocytes and failures of cancer inhibition mechanisms. Several aurora kinase inhibitions have been studied in vitro and in vivo. A number of new aurora kinase inhibitors are being development of numerous aurora kinase inhibitors is likely to increase the number of selectable drugs during treatment. This review showed that different methodology toward the development of aurora kinase inhibitors.
The functional diversity of Aurora kinases: a comprehensive review
Cell Division
Aurora kinases are serine/threonine kinases essential for the onset and progression of mitosis. Aurora members share a similar protein structure and kinase activity, but exhibit distinct cellular and subcellular localization. AurA favors the G2/M transition by promoting centrosome maturation and mitotic spindle assembly. AurB and AurC are chromosome-passenger complex proteins, crucial for chromosome binding to kinetochores and segregation of chromosomes. Cellular distribution of AurB is ubiquitous, while AurC expression is mainly restricted to meiotically-active germ cells. In human tumors, all Aurora kinase members play oncogenic roles related to their mitotic activity and promote cancer cell survival and proliferation. Furthermore, AurA plays tumor-promoting roles unrelated to mitosis, including tumor stemness, epithelial-to-mesenchymal transition and invasion. In this review, we aim to understand the functional interplay of Aurora kinases in various types of human cells, including tumor cells. The understanding of the functional diversity of Aurora kinases could help to evaluate their relevance as potential therapeutic targets in cancer.
Aurora A and B Kinases - Targets of Novel Anticancer Drugs
Recent Patents on Anti-Cancer Drug Discovery, 2010
The Aurora Kinases are highly related serine-threonine kinases, essential for accurate and equal segregation of genomic material during mitosis. A large number of studies have linked the aberrant expression of Aurora kinases to cancer, leading to the development of specific Aurora kinases inhibitors. Several small molecules inhibit with a similar efficacy both Aurora A and Aurora B, however, in most cases the effects resemble Aurora B disruption by genetic methods, indicating that Aurora B represents an effective therapeutic target. These drugs are currently under preclinical or clinical evaluation and are reviewed in this article. The relevant patents are discussed.