Target Information

Target General Infomation
Target ID
T87675
Former ID
TTDC00006
Target Name
Aurora kinase A
Gene Name
AURKA
Synonyms
Aurora-A; Aurora-related kinase 1; Aurora/IPL1-related kinase 1; Breast tumor-amplified kinase; Serine/threonine kinase 15; Serine/threonine-protein kinase 6; hARK1; AURKA
Target Type
Clinical Trial
Disease Acute myeloid leukemia [ICD9: 205; ICD10: C92.0]
Advanced solid tumor [ICD9: 140-199; ICD10: C00-C75, C7A, C7B]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Haematological malignancies [ICD9: 200-209; ICD10: C81-C86]
Late-stage solid tumors [ICD9: 140-199, 210-229; ICD10: C00-C75, C7A, C7B, D10-D36, D3A]
Prostate cancer [ICD9: 185; ICD10: C61]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Function
Mitotic serine/threonine kinases that contributes to the regulation of cell cycle progression. Associates with the centrosome and the spindle microtubules during mitosis and plays a critical role in various mitotic events including the establishment of mitotic spindle, centrosome duplication, centrosome separation as well as maturation, chromosomal alignment, spindle assembly checkpoint, and cytokinesis. Required for initial activation of CDK1 at centrosomes. Phosphorylates numerous target proteins, including ARHGEF2, BORA, BRCA1, CDC25B, DLGP5, HDAC6, KIF2A, LATS2, NDEL1, PARD3, PPP1R2, PLK1, RASSF1, TACC3, p53/TP53 and TPX2. Regulates KIF2A tubulin depolymerase activity. Required for normal axon formation. Plays a role in microtubule remodeling during neurite extension. Important for microtubule formation and/or stabilization. Also acts as a key regulatory component of the p53/TP53 pathway, and particularly the checkpoint-response pathways critical for oncogenic transformation of cells, by phosphorylating and stabilizing p53/TP53. Phosphorylates its own inhibitors, the protein phosphatase type 1 (PP1) isoforms, to inhibit their activity. Necessary for proper cilia disassembly prior to mitosis.
BioChemical Class
Kinase
Target Validation
T87675
UniProt ID
O14965
EC Number
EC 2.7.11.1
Sequence
MDRSKENCISGPVKATAPVGGPKRVLVTQQFPCQNPLPVNSGQAQRVLCPSNSSQRVPLQ
AQKLVSSHKPVQNQKQKQLQATSVPHPVSRPLNNTQKSKQPLPSAPENNPEEELASKQKN
EESKKRQWALEDFEIGRPLGKGKFGNVYLAREKQSKFILALKVLFKAQLEKAGVEHQLRR
EVEIQSHLRHPNILRLYGYFHDATRVYLILEYAPLGTVYRELQKLSKFDEQRTATYITEL
ANALSYCHSKRVIHRDIKPENLLLGSAGELKIADFGWSVHAPSSRRTTLCGTLDYLPPEM
IEGRMHDEKVDLWSLGVLCYEFLVGKPPFEANTYQETYKRISRVEFTFPDFVTEGARDLI
SRLLKHNPSQRPMLREVLEHPWITANSSKPSNCQNKESASKQS
Drugs and Mode of Action
Drug(s) AT9283 Drug Info Phase 3 Solid tumours [1], [2]
MLN8237 Drug Info Phase 3 Cancer [3], [4]
ENMD-2076 Drug Info Phase 2 Acute myeloid leukemia [5], [6]
PHA-739358 Drug Info Phase 2 Prostate cancer [7], [8]
VX-680 Drug Info Phase 2 Solid tumours [9], [10]
AMG 900 Drug Info Phase 1 Solid tumours [11], [12]
CYC116 Drug Info Phase 1 Solid tumours [13]
MK-5108 Drug Info Phase 1 Cancer [14], [15]
MLN8054 Drug Info Phase 1 Solid tumours [16], [17]
R763 Drug Info Phase 1 Haematological malignancies [18]
SNS-314 Drug Info Phase 1 Solid tumours [19]
SU-6668 Drug Info Phase 1 Advanced solid tumor [20], [21]
TAS-119 Drug Info Phase 1 Late-stage solid tumors [22]
PF-03814735 Drug Info Discontinued in Phase 1 Advanced solid tumor [23]
Inhibitor 2-(1H-pyrazol-3-yl)-1H-benzimidazole Drug Info [24]
4-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine Drug Info [25]
6-bromoindirubin-3-oxime Drug Info [26]
7-fluoroindirubin-3-oxime Drug Info [26]
Adenosine-5'-Diphosphate Drug Info [27]
CYC116 Drug Info [28]
ENMD-2076 Drug Info [29]
Indirubin-3-acetoxime Drug Info [26]
Indirubin-3-methoxime Drug Info [26]
Indirubin-3-oxime Drug Info [26]
MK-5108 Drug Info [30], [31]
MLN8054 Drug Info [32], [33], [34]
MLN8237 Drug Info [35]
PF-03814735 Drug Info [29]
PHA-739358 Drug Info [29]
Phosphonothreonine Drug Info [36]
R763 Drug Info [37]
SNS-314 Drug Info [38], [39], [40], [41]
SU-6668 Drug Info [42], [33]
TAS-119 Drug Info [43]
VX-680 Drug Info [33], [44]
ZM-447439 Drug Info [45]
Modulator AMG 900 Drug Info [11]
AT9283 Drug Info [1]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Oocyte meiosis
Pathway Interaction Database Aurora B signaling
Signaling by Aurora kinases
Integrin-linked kinase signaling
PLK1 signaling events
Aurora A signaling
Reactome Cdh1 targeted proteins in late mitosis/early G1
Regulation of PLK1 Activity at G2/M Transition
WikiPathways EGF/EGFR Signaling Pathway
JAK/STAT
Gastric Cancer Network 1
Integrated Breast Cancer Pathway
APC/C-mediated degradation of cell cycle proteins
References
REF 1A phase I trial of AT9283 (a selective inhibitor of aurora kinases) in children and adolescents with solid tumors: a Cancer Research UK study. Clin Cancer Res. 2015 Jan 15;21(2):267-73.
REF 2(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7949).
REF 3ClinicalTrials.gov (NCT01482962) Alisertib (MLN8237) or Investigator's Choice in Patients With Relapsed/Refractory Peripheral T-Cell Lymphoma. U.S. National Institutes of Health.
REF 4(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7790).
REF 5ENMD-2076 is an orally active kinase inhibitor with antiangiogenic and antiproliferative mechanisms of action. Mol Cancer Ther. 2011 Jan;10(1):126-37.
REF 6(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7885).
REF 7(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7937).
REF 8Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025382)
REF 9Nat Med. 2004 Mar;10(3):262-7. Epub 2004 Feb 22.VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo.
REF 10(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5718).
REF 11Preclinical evaluation of AMG 900, a novel potent and highly selective pan-aurora kinase inhibitor with activity in taxane-resistant tumor cell lines. Cancer Res. 2010 Dec 1;70(23):9846-54.
REF 12(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8060).
REF 13ClinicalTrials.gov (NCT00560716) A Phase I Pharmacologic Study of CYC116, an Oral Aurora Kinase Inhibitor, in Patients With Advanced Solid Tumors. U.S. National Institutes of Health.
REF 14(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8061).
REF 15Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026594)
REF 16ClinicalTrials.gov (NCT00652158) A Phase 1 Trial of Extended MLN8054 Dosing in Patients With Advanced Malignancies. U.S. National Institutes of Health.
REF 17(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5696).
REF 18Clinical pipeline report, company report or official report of Rigel.
REF 19ClinicalTrials.gov (NCT00519662) Safety and Tolerability Study of SNS-314 for Advanced Solid Tumors. U.S. National Institutes of Health.
REF 20A phase I surrogate endpoint study of SU6668 in patients with solid tumors. Invest New Drugs. 2004 Nov;22(4):459-66.
REF 21(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7816).
REF 22Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800040598)
REF 23Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025628)
REF 24The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
REF 25Bioorg Med Chem Lett. 2010 Apr 15;20(8):2552-5. Epub 2010 Mar 1.Discovery of a new series of Aurora inhibitors through truncation of GSK1070916.
REF 26J Med Chem. 2007 Aug 23;50(17):4027-37. Epub 2007 Aug 1.An integrated computational approach to the phenomenon of potent and selective inhibition of aurora kinases B and C by a series of 7-substituted indirubins.
REF 27DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-4. Nucleic Acids Res. 2011 January
REF 28Clinical pipeline report, company report or official report of Cyclacel.
REF 29Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
REF 30A novel c-Met inhibitor, MK8033, synergizes with carboplatin plus paclitaxel to inhibit ovarian cancer cell growth. Oncol Rep. 2013 May;29(5):2011-8.
REF 31Anticancer activity of the Aurora A kinase inhibitor MK-5108 in non-small-cell lung cancer (NSCLC) in vitro as monotherapy and in combination with chemotherapies. J Cancer Res Clin Oncol. 2014 Jul;140(7):1137-49.
REF 32MLN8054, a small-molecule inhibitor of Aurora A, causes spindle pole and chromosome congression defects leading to aneuploidy. Mol Cell Biol. 2007 Jun;27(12):4513-25. Epub 2007 Apr 16.
REF 33A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. Curr Top Med Chem. 2007;7(14):1408-22.
REF 34Clinical pipeline report, company report or official report of Takeda (2009).
REF 35Effect of Aurora A kinase inhibitor MLN8237 combined with rituximab on antitumor activity in preclinical B-cell non-Hodgkin's lymphoma models. Journal of Clinical Oncology, 2009:8553.
REF 36How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
REF 37Preclinical characterization of Aurora kinase inhibitor R763/AS703569 identified through an image-based phenotypic screen. J Cancer Res Clin Oncol. 2009 Jul 17.
REF 38Water-soluble prodrugs of an Aurora kinase inhibitor. Bioorg Med Chem Lett. 2009 Mar 1;19(5):1409-12. Epub 2009 Jan 19.
REF 39Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2009 Jan-Feb;31(1):47-57.
REF 40The Aurora kinase inhibitor SNS-314 shows broad therapeutic potential with chemotherapeutics and synergy with microtubule-targeted agents in a colon carcinoma model. Mol Cancer Ther. 2009 Apr;8(4):930-9.
REF 41SNS-314, a pan-Aurora kinase inhibitor, shows potent anti-tumor activity and dosing flexibility in vivo. Cancer Chemother Pharmacol. 2009 Aug 1.
REF 42Dose-finding study of the multitargeted tyrosine kinase inhibitor SU6668 in patients with advanced malignancies. Clin Cancer Res. 2005 Sep 1;11(17):6240-6.
REF 43TAS-119, a selective Aurora A inhibitor, enhanced the antitumor efficacy of taxanes in multiple human tumor cell lines including paclitaxel-resistant cells. Molecular Cancer Therapeutics. 01/2014; 12(11_Supplement):A268-A268.
REF 44Essential roles of mTOR/Akt pathway in Aurora-A cell transformation. Int J Biol Sci. 2009 Jun 19;5(5):444-50.
REF 45J Med Chem. 2006 Aug 10;49(16):4805-8.Accurate prediction of the relative potencies of members of a series of kinase inhibitors using molecular docking and MM-GBSA scoring.

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