Target Information
Target General Infomation | |||||
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Target ID |
T46781
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Former ID |
TTDC00139
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Target Name |
Aurora kinase B
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Gene Name |
AURKB
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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
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Target Type |
Clinical Trial
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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}.
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BioChemical Class |
Kinase
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Target Validation |
T46781
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UniProt ID | |||||
EC Number |
EC 2.7.11.1
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Sequence |
MAQKENSYPWPYGRQTAPSGLSTLPQRVLRKEPVTPSALVLMSRSNVQPTAAPGQKVMEN
SSGTPDILTRHFTIDDFEIGRPLGKGKFGNVYLAREKKSHFIVALKVLFKSQIEKEGVEH QLRREIEIQAHLHHPNILRLYNYFYDRRRIYLILEYAPRGELYKELQKSCTFDEQRTATI MEELADALMYCHGKKVIHRDIKPENLLLGLKGELKIADFGWSVHAPSLRRKTMCGTLDYL PPEMIEGRMHNEKVDLWCIGVLCYELLVGNPPFESASHNETYRRIVKVDLKFPASVPMGA QDLISKLLRHNPSERLPLAQVSAHPWVRANSRRVLPPSALQSVA |
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Structure |
4AF3
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Drugs and Mode of Action | |||||
Drug(s) | AT9283 | Drug Info | Phase 3 | Solid tumours | [533017], [542864] |
PHA-739358 | Drug Info | Phase 2 | Prostate cancer | [542852], [548410] | |
VX-680 | Drug Info | Phase 2 | Solid tumours | [526974], [541056] | |
AMG 900 | Drug Info | Phase 1 | Solid tumours | [531205], [542948] | |
BI-811283 | Drug Info | Phase 1 | Acute myeloid leukemia | [522353] | |
BI-831266 | Drug Info | Phase 1 | Solid tumours | [522440] | |
BI-847325 | Drug Info | Phase 1 | Solid tumours | [523412] | |
CYC116 | Drug Info | Phase 1 | Solid tumours | [522163] | |
GSK1070916 | Drug Info | Phase 1 | Advanced solid tumor | [543084], [549088] | |
GSK1070916A | Drug Info | Phase 1 | Solid tumours | [523030] | |
MK-5108 | Drug Info | Phase 1 | Cancer | [542949], [548558] | |
R763 | Drug Info | Phase 1 | Haematological malignancies | [549926] | |
SNS-314 | Drug Info | Phase 1 | Solid tumours | [522092] | |
SU-6668 | Drug Info | Phase 1 | Advanced solid tumor | [527156], [542760] | |
TAK-901 | Drug Info | Phase 1 | Hematological malignancies | [548836] | |
PF-03814735 | Drug Info | Discontinued in Phase 1 | Advanced solid tumor | [548451] | |
Modulator | AMG 900 | Drug Info | [531205] | ||
AT9283 | Drug Info | [533017] | |||
AZD-1152-HQPA | Drug Info | ||||
BI-831266 | Drug Info | [533088] | |||
BI-847325 | Drug Info | ||||
GSK1070916 | Drug Info | [530869] | |||
GSK1070916A | Drug Info | [525366], [530869] | |||
Inhibitor | BI-811283 | Drug Info | [531806], [544271] | ||
CYC116 | Drug Info | [550374] | |||
MK-5108 | Drug Info | [549718], [550064] | |||
PF-03814735 | Drug Info | [537564] | |||
PHA-739358 | Drug Info | [537564] | |||
R763 | Drug Info | [537610] | |||
SNS-314 | Drug Info | [537044], [537212], [537234], [537635] | |||
SU-6668 | Drug Info | [536137], [536474] | |||
TAK-901 | Drug Info | [551717] | |||
VX-680 | Drug Info | [536474], [537553] | |||
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 522092 | ClinicalTrials.gov (NCT00519662) Safety and Tolerability Study of SNS-314 for Advanced Solid Tumors. U.S. National Institutes of Health. | ||||
Ref 522163 | ClinicalTrials.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 522353 | ClinicalTrials.gov (NCT00701324) BI 811283 in Various Solid Tumours. U.S. National Institutes of Health. | ||||
Ref 522440 | ClinicalTrials.gov (NCT00756223) Phase I Study of BI 831266 in Patients With Advanced Solid Tumours. U.S. National Institutes of Health. | ||||
Ref 523030 | ClinicalTrials.gov (NCT01118611) Aurora B/C Kinase Inhibitor GSK1070916A in Treating Patients With Advanced Solid Tumors. U.S. National Institutes of Health. | ||||
Ref 523412 | ClinicalTrials.gov (NCT01324830) Monotherapy Dose Finding With BI 847325 in Solid Tumours. U.S. National Institutes of Health. | ||||
Ref 526974 | Nat 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 527156 | A phase I surrogate endpoint study of SU6668 in patients with solid tumors. Invest New Drugs. 2004 Nov;22(4):459-66. | ||||
Ref 531205 | Preclinical 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 533017 | A 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 541056 | (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 542760 | (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 542852 | (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 542864 | (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 542948 | (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 542949 | (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 543084 | (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 548410 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025382) | ||||
Ref 548451 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025628) | ||||
Ref 548558 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026594) | ||||
Ref 548836 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029358) | ||||
Ref 525366 | GSK1070916, 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 530869 | J Med Chem. 2010 May 27;53(10):3973-4001.Discovery of GSK1070916, a potent and selective inhibitor of Aurora B/C kinase. | ||||
Ref 531205 | Preclinical 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 531806 | Aurora kinase inhibitors: progress towards the clinic. Invest New Drugs. 2012 Dec;30(6):2411-32. | ||||
Ref 533017 | A 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 533088 | A 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 536137 | Dose-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 536474 | A 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 537044 | Water-soluble prodrugs of an Aurora kinase inhibitor. Bioorg Med Chem Lett. 2009 Mar 1;19(5):1409-12. Epub 2009 Jan 19. | ||||
Ref 537234 | The 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 537553 | Essential roles of mTOR/Akt pathway in Aurora-A cell transformation. Int J Biol Sci. 2009 Jun 19;5(5):444-50. | ||||
Ref 537564 | Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66. | ||||
Ref 537610 | Preclinical characterization of Aurora kinase inhibitor R763/AS703569 identified through an image-based phenotypic screen. J Cancer Res Clin Oncol. 2009 Jul 17. | ||||
Ref 537635 | SNS-314, a pan-Aurora kinase inhibitor, shows potent anti-tumor activity and dosing flexibility in vivo. Cancer Chemother Pharmacol. 2009 Aug 1. | ||||
Ref 544271 | Aurora kinase inhibitors: Progress towards the clinic. Invest New Drugs. 2012 December; 30(6): 2411-2432. | ||||
Ref 549718 | A novel c-Met inhibitor, MK8033, synergizes with carboplatin plus paclitaxel to inhibit ovarian cancer cell growth. Oncol Rep. 2013 May;29(5):2011-8. |
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