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. Dar et al. Page 16 Mol Cancer Ther. Author manuscript, available in PMC 2011 February 2. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript IC-87114 Figure 2. Overview of the different effects that are observed upon over expression and/or amplification of AURKA. Dar et al. Page 17 Mol Cancer Ther. Author manuscript, available in PMC 2011 February 2. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript Figure 3. Schematic representation of AURKA interactions. AURKA over expression inhibits p53 family members and suppresses apoptosis and cell cycle arrest. AURKA interacts directly with p53 by phosphorylating it at Ser215 and 315 causing its degradation through MDM2 or inactivating it at transcription level, respectively. AURKA regulates p73 and its downstream targets .
It also up regulates the PI3 kinase pathway that enhances cell survival and proliferation either directly interacting with GSK 3β or by regulating AKT . Dar et al. Page 18 Mol Cancer Ther. Author manuscript, available MK-2206 in PMC 2011 February 2. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript Dar et al. Page 19 Table 1 Aurora kinase inhibitors in clinical trials* Inhibitor AURKA inhibition AURKB inhibition AURKC inhibition Manufacturer Clinical Status AZD1152 + + ?Astra Zeneca Phase I VX 680 + + + Vertex/Merck Discontinued MLN8054 + + ?Millinnium Discontinued MLN8237 + + ?Millinnium Phase II PHA 680632 + + Nerviano Preclinical PHA 739358 + + + Nerviano Phase II Hesperidin ?+ ?Boehringer Ingelhiem Preclinical ZM447439 + + ?Astra Zeneca Phase I JNJ 770621 + + ?Johnson & Johnson Preclinical SU6668 + + ?Pfizer Discontinued CCT129202 + + + Chroma Therapeutics Ltd.
Preclinical AT9283 + + ?Astrex Therapeutics Phase I MP529 + + ?Supregen Preclinical SNS314 + + + Sunesis Pharmaceuticals Phase I R763 ?+ ?Rigel Pharmaceuticals Phase I ENMD2076 + + ?EntreMed Phase I XL228 + + + Exelixis Phase I TTP607 + + + TransTech Pharma Phase I PF 03814735 + + ?Pfizer Phase I CYC116 + + + Cyclacel Phase I * The source of data is clinicaltrial.gov Mol Cancer Ther. Author manuscript, available in PMC 2011 February 2. Update on Aurora Kinase Targeted Therapeutics in Oncology Myke R. Green, BS, Pharm.D., BCOP1,2, Joseph E. Woolery, BS, Pharm.D.
3,4, and Daruka Mahadevan, MD, PhD1 1 Section of Hematology/Oncology, Arizona Cancer Center, Tucson, AZ 2 Department of Pharmacy Services, University Medical Center, Tucson, AZ 3 Division of Hematology, University of Texas M. D. Anderson Cancer Center, Houston, TX 4 Department of Pharmacy Services, University of Texas M. D. Anderson Cancer Center, Houston, TX Abstract 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. Areas covered This review provides the reader with updated results from both preclinical and human studies for each of the aurora kinase inhibitors that are currently being investigated. The paper also covers in detail the late breaking and phase I data presented for AKIs thereby allowing the reader to compare and contrast individual and classrelated effects of AKIs. Expert opinion—While the successful development and approval of an AKI for anti cancer therapy remains unresolved, pre clinical identification of resistant mechanisms would help design better early phase clinical trials where relevant combina