The Aurora kinase inhibitors in cancer research and therapy (original) (raw)
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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.
Aurora kinases and their inhibitors: more than one target and one drug
Advances in experimental medicine and biology, 2008
Dependent on the degree of inhibition of different Aurora kinase family members, various events in mitosis are affected, resulting in differential cellular responses. These different cellular responses have to be considered in the clinical development of the small molecule inhibitors with respect to the chosen indications, schedules and appropriate endpoints. Here the properties of the most advanced small molecule Aurora kinase inhibitors are compared and a case report on the development of PHA-739358 - a spectrum selective kinases inhibitor with a dominant phenotype of Aurora kinases inhibition, which is currently being tested in clinical trials - is discussed. One of the selection criteria for this compound was its property of inhibiting more than one cancer relevant target, such as Abl wild-type and the multidrug resistant Abl T315I mutant. This opens another path for clinical development in CML, and clinical trials are underway to evaluate the activity in patients suffering from...
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.
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.
Biology of Aurora A kinase: Implications in cancer manifestation and therapy
Medicinal Research Reviews, 2010
The Aurora A kinase belongs to serine/threonine group of kinases, well known for its role in cell cycle, especially in the regulation of mitosis. Numerous substrates of Aurora A kinase have been identified, which are predominantly related to cell cycle progression while some of them are transcription factors. Aurora A-mediated phosphorylation can either directly or indirectly regulate the function of its substrates. There are overwhelming evidences which report overexpression and gene amplification of Aurora A in several human cancers, and suggest that Aurora A could be a bona fide oncogene involved in tumorigenesis. Hence, Aurora A plays wide-ranging roles in both mitosis and its deregulation manifests in cancer progression. These observations have favored the choice of Aurora kinases as a target for cancer therapy. Recently, numerous small molecules have been discovered against Aurora kinases and many have entered clinical trials. Most of these small-molecule modulators designed are specific against either Aurora A or Aurora B, but some are dual inhibitors targeting the ATP-binding site which is highly conserved among the three human homologues of Aurora kinase. In this review, we discuss the physiological functions of Aurora A, interactions between Aurora A kinase and its cellular substrates, tumorigenesis mediated by Aurora A kinase upon overexpression, and small-molecule modulators of Aurora kinase as targets for cancer therapy.
Molecular cancer …, 2007
PHA-739358 is a small-molecule 3-aminopyrazole derivative with strong activity against Aurora kinases and cross-reactivities with some receptor tyrosine kinases relevant for cancer. PHA-739358 inhibits all Aurora kinase family members and shows a dominant Aurora B kinase inhibition-related cellular phenotype and mechanism of action in cells in vitro and in vivo. p53 status-dependent endoreduplication is observed upon treatment of cells with PHA-739358, and phosphorylation of histone H3 in Ser(10) is inhibited. The compound has significant antitumor activity in different xenografts and spontaneous and transgenic animal tumor models and shows a favorable pharmacokinetic and safety profile. In vivo target modulation is observed as assessed by the inhibition of the phosphorylation of histone H3, which has been validated preclinically as a candidate biomarker for the clinical phase. Pharmacokinetics/pharmacodynamics modeling was used to define drug potency and to support the prediction o...
Aurora Kinases and Passenger Proteins as Targets for Cancer Therapy: An Update
Current Enzyme Inhibition, 2010
Aurora kinases play pivotal role in mitosis. Aurora kinase A controls centrosome duplication, spindle pole integrity as well as bipolar spindle formation. Aurora kinase B is part of the chromosome passenger complex (CPC) and through its co-factors, drives chromosome congression, bidirectional tension on kinetochores and spindle checkpoint signaling, as well as cytokinesis completion. Both CPC and Aurora kinases are exclusively expressed during mitosis and are up regulated in many tumors. Their overexpression correlates with the level of genomic instability within tumors and these proteins are therefore proposed as potential targets for cancer therapy. This review describes the interplay between Aurora kinases in mitosis and the different strategies that have been developed towards their targeting. ?? 2010. Index Keywords: 1 cyclopropyl 3 [3 (5 morpholinomethyl 1h benzimidazol 2 yl) 1h pyrazol 4 yl]urea; 2 [[3 [4 [5 [2 (3 fluoroanilino) 2 oxoethyl] 1h pyrazol 3 ylamino] 7 quinazolinyloxy]propyl](ethyl)amino]ethyl dihydrogen phosphate; 4 [[9 chloro 7 (2,6 difluorophenyl) 5h pyrimido[5,4 d][2]benzazepin 2 yl]amino]benzoic acid; aki 001; amg 900; as 703569; aurora A kinase; aurora B kinase; aurora kinase inhibitor; c 1; chromosome protein; cyc 116; cyclopropanecarboxylic acid [4 [4 (4 methyl 1 piperazinyl) 6 (5 methyl 2h pyrazol 3 ylamino) 2 pyrimidinylthio]phenyl]amide; danusertib; enmd 2076; gsk 1070916; mk 6592; mln 8237; mp 529; om 137; pf 03814735; pha 60632; pha 680632; protein borealin; protein telophase disc 60Chemicals/CAS: cyclopropanecarboxylic acid [4 [4 (4 methyl 1 piperazinyl) 6 (5 methyl 2h pyrazol 3 ylamino) 2 pyrimidinylthio]phenyl]
Aurora kinases as targets for cancer therapy
Cancer Treatment Reviews, 2008
Aurora kinases represent a family of serine/threonine kinases highly conserved during evolution, whose main function is to promote mitotic spindle assembly by regulating centrosome duplication and separation. Inhibition of Aurora kinase activity may lead to defects in centrosome function, misaligned sister chromatides, mitotic spindle malformation, problematic cytokinesis and eventually mitotic arrest. Aurora kinases are overexpressed in a variety of tumor cell lines, suggesting their potential role in tumorigenesis and indicating that they could represent an appealing target for molecular therapies. Extensive pre-clinical information supports the development of Aurora kinase inhibitors in specific tumor types and a number of these novel agents are currently being extensively studied in phase I and II clinical trials exhibiting an acceptable toxicity profile and promising clinical efficacy. The current study aims to provide a comprehensive overview of the development of Aurora kinases as molecular targets for anticancer therapy by focusing on their physiological role in mitosis, their implication in oncogenesis and the potential ways of inhibiting their activity. The main pre-clinical and clinical studies concerning Aurora kinase inhibitors currently under investigation are reported and important considerations for their future development are discussed.