Target Information
| Target General Information | Top | |||||
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| Target ID |
T46781
(Former ID: TTDC00139)
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| Target Name |
Aurora kinase B (AURKB)
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| Synonyms |
Serine/threonine-protein kinase aurora-B; Serine/threonine-protein kinase 5; Serine/threonine-protein kinase 12; Serine/threonine protein kinase 12; STK5; STK12; Aurora/IPL1-related kinase 2; Aurora-related kinase 2; Aurora-B; Aurora-2 kinase; Aurora-2; Aurora- and Ipl1-like midbody-associated protein 1; Aurora 1; ARK2; ARK-2; AIRK2; AIM1; AIM-1; AIK2
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| Gene Name |
AURKB
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Acute diabete complication [ICD-11: 5A2Y] | |||||
| 2 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
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. 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, HASPIN, and histone H3. A positive feedback loop involving HASPIN 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 HASPIN and AURKB contributes to CPC localization. AURKB is also required for kinetochore localization of BUB1 and SGO1. Phosphorylation of p53/TP53 negatively regulates its transcriptional activity. Key regulator of active promoters in resting 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. Serine/threonine-protein kinase component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.11.1
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| Sequence |
MAQKENSYPWPYGRQTAPSGLSTLPQRVLRKEPVTPSALVLMSRSNVQPTAAPGQKVMEN
SSGTPDILTRHFTIDDFEIGRPLGKGKFGNVYLAREKKSHFIVALKVLFKSQIEKEGVEH QLRREIEIQAHLHHPNILRLYNYFYDRRRIYLILEYAPRGELYKELQKSCTFDEQRTATI MEELADALMYCHGKKVIHRDIKPENLLLGLKGELKIADFGWSVHAPSLRRKTMCGTLDYL PPEMIEGRMHNEKVDLWCIGVLCYELLVGNPPFESASHNETYRRIVKVDLKFPASVPMGA QDLISKLLRHNPSERLPLAQVSAHPWVRANSRRVLPPSALQSVA Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T01E7W | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 18 Clinical Trial Drugs | + | ||||
| 1 | AT9283 | Drug Info | Phase 3 | Solid tumour/cancer | [1], [2] | |
| 2 | Rosiglitazone + metformin | Drug Info | Phase 3 | Diabetic complication | [3] | |
| 3 | ABT-348 | Drug Info | Phase 2 | Haematological malignancy | [4] | |
| 4 | PHA-739358 | Drug Info | Phase 2 | Prostate cancer | [5], [6] | |
| 5 | VX-680 | Drug Info | Phase 2 | Solid tumour/cancer | [7], [8] | |
| 6 | AMG 900 | Drug Info | Phase 1 | Solid tumour/cancer | [9], [10] | |
| 7 | AZD-1152-HQPA | Drug Info | Phase 1 | Solid tumour/cancer | [11] | |
| 8 | BI-811283 | Drug Info | Phase 1 | Acute myeloid leukaemia | [12] | |
| 9 | BI-831266 | Drug Info | Phase 1 | Solid tumour/cancer | [13] | |
| 10 | BI-847325 | Drug Info | Phase 1 | Solid tumour/cancer | [14] | |
| 11 | CYC116 | Drug Info | Phase 1 | Solid tumour/cancer | [15] | |
| 12 | GSK1070916 | Drug Info | Phase 1 | Advanced solid tumour | [16], [17] | |
| 13 | GSK1070916A | Drug Info | Phase 1 | Solid tumour/cancer | [18] | |
| 14 | HPP-607 | Drug Info | Phase 1 | Solid tumour/cancer | [19] | |
| 15 | MK-5108 | Drug Info | Phase 1 | Solid tumour/cancer | [20] | |
| 16 | R763 | Drug Info | Phase 1 | Haematological malignancy | [21] | |
| 17 | SNS-314 | Drug Info | Phase 1 | Solid tumour/cancer | [22] | |
| 18 | TAK-901 | Drug Info | Phase 1 | Haematological malignancy | [23] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | PF-03814735 | Drug Info | Discontinued in Phase 1 | Advanced solid tumour | [24] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Modulator | [+] 8 Modulator drugs | + | ||||
| 1 | AT9283 | Drug Info | [1] | |||
| 2 | ABT-348 | Drug Info | [27] | |||
| 3 | AMG 900 | Drug Info | [10] | |||
| 4 | AZD-1152-HQPA | Drug Info | [30] | |||
| 5 | BI-831266 | Drug Info | [33] | |||
| 6 | BI-847325 | Drug Info | [34] | |||
| 7 | GSK1070916 | Drug Info | [36] | |||
| 8 | GSK1070916A | Drug Info | [36], [37] | |||
| Inhibitor | [+] 11 Inhibitor drugs | + | ||||
| 1 | Rosiglitazone + metformin | Drug Info | [25], [26] | |||
| 2 | PHA-739358 | Drug Info | [28] | |||
| 3 | VX-680 | Drug Info | [25], [29] | |||
| 4 | BI-811283 | Drug Info | [31], [32] | |||
| 5 | CYC116 | Drug Info | [35] | |||
| 6 | HPP-607 | Drug Info | [38] | |||
| 7 | MK-5108 | Drug Info | [39], [40] | |||
| 8 | R763 | Drug Info | [41] | |||
| 9 | SNS-314 | Drug Info | [42], [43], [44], [45] | |||
| 10 | TAK-901 | Drug Info | [46] | |||
| 11 | PF-03814735 | Drug Info | [28] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: VX-680 | Ligand Info | |||||
| Structure Description | Human Aurora B Kinase in complex with INCENP and VX-680 | PDB:4AF3 | ||||
| Method | X-ray diffraction | Resolution | 2.75 Å | Mutation | Yes | [47] |
| PDB Sequence |
RHFTIDDFEI
79 GRPLGKGKFG89 NVYLAREKKS99 HFIVALKVLF109 KSQIEKEGVE119 HQLRREIEIQ 129 AHLHHPNILR139 LYNYFYDRRR149 IYLILEYAPR159 GELYKELQKS169 CTFDEQRTAT 179 IMEELADALM189 YCHGKKVIHR199 DIKPENLLLG209 LKGELKIADF219 GLDYLPPEMI 245 EGRMHNEKVD255 LWCIGVLCYE265 LLVGNPPFES275 ASHNETYRRI285 VKVDLKFPAS 295 VPTGAQDLIS305 KLLRHNPSER315 LPLAQVSAHP325 WVRANSRRVL335 PPS |
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Biological Network Descriptors
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| Degree | 55 | Degree centrality | 5.91E-03 | Betweenness centrality | 2.08E-03 |
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| Closeness centrality | 2.25E-01 | Radiality | 1.40E+01 | Clustering coefficient | 3.28E-01 |
| Neighborhood connectivity | 3.29E+01 | Topological coefficient | 8.36E-02 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-interacting Proteins | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| PID Pathway | [+] 5 PID Pathways | + | ||||
| 1 | Aurora B signaling | |||||
| 2 | Signaling by Aurora kinases | |||||
| 3 | Aurora C signaling | |||||
| 4 | FOXM1 transcription factor network | |||||
| 5 | Aurora A signaling | |||||
| Reactome | [+] 5 Reactome Pathways | + | ||||
| 1 | APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1 | |||||
| 2 | Separation of Sister Chromatids | |||||
| 3 | Resolution of Sister Chromatid Cohesion | |||||
| 4 | RHO GTPases Activate Formins | |||||
| 5 | Mitotic Prometaphase | |||||
| WikiPathways | [+] 6 WikiPathways | + | ||||
| 1 | Mitotic Metaphase and Anaphase | |||||
| 2 | Mitotic Prometaphase | |||||
| 3 | Regulation of Microtubule Cytoskeleton | |||||
| 4 | miR-targeted genes in lymphocytes - TarBase | |||||
| 5 | miR-targeted genes in epithelium - TarBase | |||||
| 6 | APC/C-mediated degradation of cell cycle proteins | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | 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 2 | URL: 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 | ClinicalTrials.gov (NCT00499707) Efficacy and Safety Study of Rosiglitazone/Metformin Therapy vs Rosiglitazone and Metformin in Type 2 Diabetes Subjects. U.S. National Institutes of Health. | |||||
| REF 4 | ClinicalTrials.gov (NCT02478320) Phase II Study of Ilorasertib (ABT348) in Patients With CDKN2A Deficient Solid Tumors. | |||||
| REF 5 | URL: 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 6 | 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 7 | URL: 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 8 | VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nat Med. 2004 Mar;10(3):262-7. | |||||
| REF 9 | URL: 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 10 | 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 11 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 12 | ClinicalTrials.gov (NCT00701324) BI 811283 in Various Solid Tumours. U.S. National Institutes of Health. | |||||
| REF 13 | ClinicalTrials.gov (NCT00756223) Phase I Study of BI 831266 in Patients With Advanced Solid Tumours. U.S. National Institutes of Health. | |||||
| REF 14 | ClinicalTrials.gov (NCT01324830) Monotherapy Dose Finding With BI 847325 in Solid Tumours. U.S. National Institutes of Health. | |||||
| REF 15 | 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 16 | URL: 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 17 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800032133) | |||||
| REF 18 | ClinicalTrials.gov (NCT01118611) Aurora B/C Kinase Inhibitor GSK1070916A in Treating Patients With Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 19 | ClinicalTrials.gov (NCT00939172) TTP607 in Refractory Solid Malignancies. U.S. National Institutes of Health. | |||||
| REF 20 | ClinicalTrials.gov (NCT00543387) Treatment of Participants With Advanced and/or Refractory Solid Tumors (MK-5108-001 AM4). U.S. National Institutes of Health. | |||||
| REF 21 | Clinical pipeline report, company report or official report of Rigel. | |||||
| REF 22 | ClinicalTrials.gov (NCT00519662) Safety and Tolerability Study of SNS-314 for Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 23 | 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 24 | 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 25 | 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 26 | 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 27 | Preclinical characterization of ABT-348, a kinase inhibitor targeting the aurora, vascular endothelial growth factor receptor/platelet-derived growth factor receptor, and Src kinase families. J Pharmacol Exp Ther. 2012 Dec;343(3):617-27. | |||||
| REF 28 | Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66. | |||||
| REF 29 | Essential roles of mTOR/Akt pathway in Aurora-A cell transformation. Int J Biol Sci. 2009 Jun 19;5(5):444-50. | |||||
| REF 30 | Phase I study of barasertib (AZD1152), a selective inhibitor of Aurora B kinase, in patients with advanced solid tumors.Invest New Drugs.2013 Apr;31(2):370-80. | |||||
| REF 31 | Aurora kinase inhibitors: progress towards the clinic. Invest New Drugs. 2012 Dec;30(6):2411-32. | |||||
| REF 32 | Aurora kinase inhibitors: Progress towards the clinic. Invest New Drugs. 2012 December; 30(6): 2411-2432. | |||||
| REF 33 | 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 34 | doi: 10.1158/1535-7163.TARG-13-B281 | |||||
| REF 35 | Clinical pipeline report, company report or official report of Cyclacel. | |||||
| REF 36 | Discovery of GSK1070916, a potent and selective inhibitor of Aurora B/C kinase. J Med Chem. 2010 May 27;53(10):3973-4001. | |||||
| REF 37 | 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 38 | URL: 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. (Target id: 1936). | |||||
| REF 39 | 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. | |||||
| REF 40 | Anticancer 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 41 | Preclinical characterization of Aurora kinase inhibitor R763/AS703569 identified through an image-based phenotypic screen. J Cancer Res Clin Oncol. 2010 Jan;136(1):99-113. | |||||
| REF 42 | SNS-314, a pan-Aurora kinase inhibitor, shows potent anti-tumor activity and dosing flexibility in vivo. Cancer Chemother Pharmacol. 2010 Mar;65(4):707-17. | |||||
| REF 43 | 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 44 | Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2009 Jan-Feb;31(1):47-57. | |||||
| REF 45 | Water-soluble prodrugs of an Aurora kinase inhibitor. Bioorg Med Chem Lett. 2009 Mar 1;19(5):1409-12. | |||||
| REF 46 | Clinical pipeline report, company report or official report of Takeda (2009). | |||||
| REF 47 | Crystal structure of human aurora B in complex with INCENP and VX-680. J Med Chem. 2012 Sep 13;55(17):7841-8. | |||||
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