tions may be evaluated prior ZSTK474 to phase II testing. The authors believe that aurora kinases are important anti cancer targets that operate in collaboration with other oncogenes intimately involved in uncontrolled tumor proliferation and by providing a unique, targeted and complimentary anti cancer mechanism, expand the available armamentarium against cancer. Correspondence to: Daruka Mahadevan. Myke R. Green, BS, Pharm.D., BCOP, Oncology Clinical Pharmacy Specialist, Division of Hematology/Oncology, Arizona Cancer Center, Tucson, AZ, Department of Pharmacy Services, University Medical Center, Tucson, AZ, Postal address: 1501 N. Campbell Ave, PO Box 245009, Tucson, AZ 85724 5009, Telephone: 1 694 6127, Fax: 1 694 5164, mgreenumcaz Joseph E. Woolery, BS, Pharm.D.
, Oncology Clinical Pharmacy Specialist, Department of Hematology, University of Texas M. D. Anderson Cancer Center, Houston, TX, Department of Pharmacy Services, University of Texas M. D. Anderson Cancer Center, Houston, TX, Postal address: 1515 Holcombe Blvd, Unit 377, Houston, TX 77030, Telephone: 1 794 3201, Fax: 1 563 9952, JEWoolerymdanderson Daruka Mahadevan, M.D., Ph.D., Vismodegib Associate Professor of Medicine, Division of Hematology/Oncology, Arizona Cancer Center, Tucson, AZ, Director, Drug Development and Translational Research Director, Phase I program, Postal address: 3838 N. Campbell Ave, Tucson, AZ 85719, Telephone: 1 694 0191, Fax: 1 626 2225, dmahadevanazcc.arizona Declaration of Interest The authors declare financial support in the form of the Lymphoma SPORE grant awarded by the National Institutes of Health and the National Cancer Institute.
The authors declare that they have no further disclosures. NIH Public Access Author Manuscript Expert Opin Drug Discov. Author manuscript, available in PMC 2012 March 1. Published in final edited form as: Expert Opin Drug Discov. 2011 March , 6: 291 307. doi:10.1517/17460441.2011.555395. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript Keywords Mitosis, Centrosome assembly, Aurora kinase inhibitor , Small molecule inhibitors, Targeted cancer therapy, Spindle assembly checkpoint, Aneuploidy 1.0 Introduction The blight of cancer upon humanity is unparalleled, already attaining the distinction of being the leading cause of death and economic burden worldwide.1,2 Cancer is characterized by uncontrolled proliferation leading to a malignant phenotype.
Mitosis is a critical step in the proliferation of cancer cells and involves many redundant and checkpoint systems controlling key steps of the process. The family of aurora kinases plays an important role in maintaining the fidelity of mitosis. This has fueled the theory that anticancer benefits may be derived from inhibition of aurora kinase activity and has led to the development of several aurora kinase inhibitors . 1.1 Aurora Kinases The aurora kinases are a family of oncogenic serine/threonine kinases involved in the mitotic phase of the cell cycle, acting to establish the mitotic spindle, bipolar spindle formation, alignment of centrosomes on mitotic spindle, centrosome separation, cytokinesis, and monitoring of the mitotic checkpoint.
3,4,5,6 Aurora kinases are critical for accurate and organized chromosome division and allocation to each daughter cell. Furthermore, aurora kinases are often overexpressed in tumor cells, particularly those with high growth fractions. There are three known aurora kinases in human neoplastic and nonneoplastic tissues. Aurora A and B kinases are expressed globally throughout all tissues, whereas aurora C kinase is primarily expressed in testes tissue to participate in meiosis. However recent research has linked Aurora C kinase activity with tumorigenesis in somatic tissue and may be a relevant cancer target.3,7,8 All three aurora kinases possess substantial sequence and structural homology and overlap in gene expression, catalytic domain, genomic length, and kinase activity, although the cellular functions and N
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