Target Information

Target General Infomation
Target ID
T46781
Former ID
TTDC00139
Target Name
Aurora kinase B
Gene Name
AURKB
Synonyms
AIM-1; Aurora- and Ipl1-like midbody-associated protein 1; Aurora-2; Aurora-2 kinase; Aurora-B; Aurora-related kinase 2; Aurora/IPL1-related kinase 2; STK-1; Serine/threonine protein kinase 12; AURKB
Target Type
Clinical Trial
Disease Advanced solid tumor [ICD9: 140-199; ICD10: C00-C75, C7A, C7B]
Acute myeloid leukemia [ICD9: 205; ICD10: C92.0]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Hematological malignancies [ICD9: 200-209; ICD10: C81-C86]
Haematological malignancies [ICD9: 200-209; ICD10: C81-C86]
Prostate cancer [ICD9: 185; ICD10: C61]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Function
Serine/threonine-protein kinase component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis. The CPC complex has essential functions at the centromere in ensuring correct chromosome alignment and segregation and is required for chromatin-induced microtubule stabilization and spindle assembly. Involved in the bipolar attachment of spindle microtubules to kinetochores and is a key regulator for the onset of cytokinesis during mitosis. Required for central/midzone spindle assembly and cleavage furrow formation. Key component of the cytokinesis checkpoint, a process required to delay abscission to prevent both premature resolution of intercellular chromosome bridges and accumulation of DNA damage: phosphorylates CHMP4C, leading to retain abscission- competent VPS4 (VPS4A and/or VPS4B) at the midbody ring until abscission checkpoint signaling is terminated at late cytokinesis (PubMed:22422861, PubMed:24814515). AURKB phosphorylates the CPC complex subunits BIRC5/survivin, CDCA8/borealin and INCENP. Phosphorylation of INCENP leads to increased AURKB activity. Other known AURKB substrates involved in centromeric functions and mitosis are CENPA, DES/desmin, GPAF, KIF2C, NSUN2, RACGAP1, SEPT1, VIM/vimentin, GSG2/Haspin, and histone H3. A positive feedback loop involving GSG2 and AURKB contributes to localization of CPC to centromeres. Phosphorylation of VIM controls vimentin filament segregation in cytokinetic process, whereas histone H3 is phosphorylated at 'Ser-10' and 'Ser-28' during mitosis (H3S10ph and H3S28ph, respectively). A positive feedback between GSG2 and AURKB contributes to CPC localization. AURKB is also required for kinetochore localization of BUB1 and SGOL1. Phosphorylation of p53/TP53 negatively regulates its transcriptional activity. Key regulator of active promoters inresting B- and T-lymphocytes: acts by mediating phosphorylation of H3S28ph at active promoters in resting B-cells, inhibiting RNF2/RING1B-mediated ubiquitination of histone H2A and enhancing binding and activity of the USP16 deubiquitinase at transcribed genes. {ECO:0000269|PubMed:11516652, ECO:0000269|PubMed:11756469, ECO:0000269|PubMed:11784863, ECO:0000269|PubMed:11856369, ECO:0000269|PubMed:12458200, ECO:0000269|PubMed:12686604, ECO:0000269|PubMed:12689593, ECO:0000269|PubMed:12925766, ECO:0000269|PubMed:14602875, ECO:0000269|PubMed:14610074, ECO:0000269|PubMed:14722118, ECO:0000269|PubMed:15020684, ECO:0000269|PubMed:15249581, ECO:0000269|PubMed:16103226, ECO:0000269|PubMed:17617734, ECO:0000269|PubMed:20959462, ECO:0000269|PubMed:21658950, ECO:0000269|PubMed:22422861, ECO:0000269|PubMed:24814515}.
BioChemical Class
Kinase
Target Validation
T46781
UniProt ID
Q96GD4
EC Number
EC 2.7.11.1
Sequence
MAQKENSYPWPYGRQTAPSGLSTLPQRVLRKEPVTPSALVLMSRSNVQPTAAPGQKVMEN
SSGTPDILTRHFTIDDFEIGRPLGKGKFGNVYLAREKKSHFIVALKVLFKSQIEKEGVEH
QLRREIEIQAHLHHPNILRLYNYFYDRRRIYLILEYAPRGELYKELQKSCTFDEQRTATI
MEELADALMYCHGKKVIHRDIKPENLLLGLKGELKIADFGWSVHAPSLRRKTMCGTLDYL
PPEMIEGRMHNEKVDLWCIGVLCYELLVGNPPFESASHNETYRRIVKVDLKFPASVPMGA
QDLISKLLRHNPSERLPLAQVSAHPWVRANSRRVLPPSALQSVA
Structure
4AF3
Drugs and Mode of Action
Drug(s) AT9283 Drug Info Phase 3 Solid tumours [1], [2]
PHA-739358 Drug Info Phase 2 Prostate cancer [3], [4]
VX-680 Drug Info Phase 2 Solid tumours [5], [6]
AMG 900 Drug Info Phase 1 Solid tumours [7], [8]
BI-811283 Drug Info Phase 1 Acute myeloid leukemia [9]
BI-831266 Drug Info Phase 1 Solid tumours [10]
BI-847325 Drug Info Phase 1 Solid tumours [11]
CYC116 Drug Info Phase 1 Solid tumours [12]
GSK1070916 Drug Info Phase 1 Advanced solid tumor [13], [14]
GSK1070916A Drug Info Phase 1 Solid tumours [15]
MK-5108 Drug Info Phase 1 Cancer [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]
TAK-901 Drug Info Phase 1 Hematological malignancies [22]
PF-03814735 Drug Info Discontinued in Phase 1 Advanced solid tumor [23]
Modulator AMG 900 Drug Info [7]
AT9283 Drug Info [1]
AZD-1152-HQPA Drug Info
BI-831266 Drug Info [24]
BI-847325 Drug Info
GSK1070916 Drug Info [25]
GSK1070916A Drug Info [26], [25]
Inhibitor BI-811283 Drug Info [27], [28]
CYC116 Drug Info [29]
MK-5108 Drug Info [30], [31]
PF-03814735 Drug Info [32]
PHA-739358 Drug Info [32]
R763 Drug Info [33]
SNS-314 Drug Info [34], [35], [36], [37]
SU-6668 Drug Info [38], [39]
TAK-901 Drug Info [40]
VX-680 Drug Info [39], [41]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
Pathway Interaction Database Aurora B signaling
Signaling by Aurora kinases
Aurora C signaling
FOXM1 transcription factor network
Aurora A signaling
Reactome Cdh1 targeted proteins in late mitosis/early G1
Separation of Sister Chromatids
Resolution of Sister Chromatid Cohesion
RHO GTPases Activate Formins
Mitotic Prometaphase
WikiPathways Mitotic Metaphase and Anaphase
Mitotic Prometaphase
Regulation of Microtubule Cytoskeleton
miR-targeted genes in lymphocytes - TarBase
miR-targeted genes in epithelium - TarBase
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 3(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 4Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025382)
REF 5Nat 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 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: 5718).
REF 7Preclinical 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 8(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 9ClinicalTrials.gov (NCT00701324) BI 811283 in Various Solid Tumours. U.S. National Institutes of Health.
REF 10ClinicalTrials.gov (NCT00756223) Phase I Study of BI 831266 in Patients With Advanced Solid Tumours. U.S. National Institutes of Health.
REF 11ClinicalTrials.gov (NCT01324830) Monotherapy Dose Finding With BI 847325 in Solid Tumours. U.S. National Institutes of Health.
REF 12ClinicalTrials.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 13(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: 8358).
REF 14Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800032133)
REF 15ClinicalTrials.gov (NCT01118611) Aurora B/C Kinase Inhibitor GSK1070916A in Treating Patients With Advanced Solid Tumors. U.S. National Institutes of Health.
REF 16(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 17Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026594)
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 800029358)
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 24A phase 1 dose escalation study of BI 831266, an inhibitor of Aurora kinase B, in patients with advanced solid tumors. Invest New Drugs. 2015 Apr;33(2):409-22.
REF 25J Med Chem. 2010 May 27;53(10):3973-4001.Discovery of GSK1070916, a potent and selective inhibitor of Aurora B/C kinase.
REF 26GSK1070916, a potent Aurora B/C kinase inhibitor with broad antitumor activity in tissue culture cells and human tumor xenograft models. Mol Cancer Ther. 2009 Jul;8(7):1808-17.
REF 27Aurora kinase inhibitors: progress towards the clinic. Invest New Drugs. 2012 Dec;30(6):2411-32.
REF 28Aurora kinase inhibitors: Progress towards the clinic. Invest New Drugs. 2012 December; 30(6): 2411-2432.
REF 29Clinical pipeline report, company report or official report of Cyclacel.
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 32Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
REF 33Preclinical characterization of Aurora kinase inhibitor R763/AS703569 identified through an image-based phenotypic screen. J Cancer Res Clin Oncol. 2009 Jul 17.
REF 34Water-soluble prodrugs of an Aurora kinase inhibitor. Bioorg Med Chem Lett. 2009 Mar 1;19(5):1409-12. Epub 2009 Jan 19.
REF 35Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2009 Jan-Feb;31(1):47-57.
REF 36The 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 37SNS-314, a pan-Aurora kinase inhibitor, shows potent anti-tumor activity and dosing flexibility in vivo. Cancer Chemother Pharmacol. 2009 Aug 1.
REF 38Dose-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 39A 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 40Clinical pipeline report, company report or official report of Takeda (2009).
REF 41Essential roles of mTOR/Akt pathway in Aurora-A cell transformation. Int J Biol Sci. 2009 Jun 19;5(5):444-50.

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