Target Information
| Target General Information | Top | |||||
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| Target ID |
T97592
(Former ID: TTDC00059)
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| Target Name |
Aurora kinase C (AURKC)
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| Synonyms |
Serine/threonine-protein kinase aurora-C; STK13; Aurora/Ipl1/Eg2 protein 2; Aurora/Ipl1-related kinase 3; Aurora-related kinase 3; Aurora-C; Aurora 3; ARK3; ARK-3; AIRK3; AIK3; AIE2
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| Gene Name |
AURKC
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 3 Target-related Diseases | + | ||||
| 1 | Malignant haematopoietic neoplasm [ICD-11: 2B33] | |||||
| 2 | Prostate cancer [ICD-11: 2C82] | |||||
| 3 | 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. Plays also a role in meiosis and more particularly in spermatogenesis. Has redundant cellular functions with AURKB and can rescue an AURKB knockdown. Like AURKB, AURKC phosphorylates histone H3 at 'Ser-10' and 'Ser-28'. AURKC phosphorylates the CPC complex subunits BIRC5/survivin and INCENP leading to increased AURKC activity. Phosphorylates TACC1, another protein involved in cell division, at 'Ser-228'. 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 |
MSSPRAVVQLGKAQPAGEELATANQTAQQPSSPAMRRLTVDDFEIGRPLGKGKFGNVYLA
RLKESHFIVALKVLFKSQIEKEGLEHQLRREIEIQAHLQHPNILRLYNYFHDARRVYLIL EYAPRGELYKELQKSEKLDEQRTATIIEELADALTYCHDKKVIHRDIKPENLLLGFRGEV KIADFGWSVHTPSLRRKTMCGTLDYLPPEMIEGRTYDEKVDLWCIGVLCYELLVGYPPFE SASHSETYRRILKVDVRFPLSMPLGARDLISRLLRYQPLERLPLAQILKHPWVQAHSRRV LPPCAQMAS Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 7 Clinical Trial Drugs | + | ||||
| 1 | ABT-348 | Drug Info | Phase 2 | Haematological malignancy | [2] | |
| 2 | PHA-739358 | Drug Info | Phase 2 | Prostate cancer | [3], [4] | |
| 3 | AMG 900 | Drug Info | Phase 1 | Solid tumour/cancer | [5], [6] | |
| 4 | GSK1070916 | Drug Info | Phase 1 | Advanced solid tumour | [7], [8] | |
| 5 | GSK1070916A | Drug Info | Phase 1 | Solid tumour/cancer | [9] | |
| 6 | HPP-607 | Drug Info | Phase 1 | Solid tumour/cancer | [10] | |
| 7 | SNS-314 | Drug Info | Phase 1 | Solid tumour/cancer | [11] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | MK-6592 | Drug Info | Discontinued in Phase 1 | Solid tumour/cancer | [12] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Modulator | [+] 4 Modulator drugs | + | ||||
| 1 | ABT-348 | Drug Info | [1] | |||
| 2 | AMG 900 | Drug Info | [6] | |||
| 3 | GSK1070916 | Drug Info | [14] | |||
| 4 | GSK1070916A | Drug Info | [14], [15] | |||
| Inhibitor | [+] 24 Inhibitor drugs | + | ||||
| 1 | PHA-739358 | Drug Info | [13] | |||
| 2 | HPP-607 | Drug Info | [16] | |||
| 3 | SNS-314 | Drug Info | [17], [18], [19], [20] | |||
| 4 | MK-6592 | Drug Info | [21] | |||
| 5 | 2np8 | Drug Info | [22] | |||
| 6 | 6-bromoindirubin-3-oxime | Drug Info | [23] | |||
| 7 | 7-bromoindirubin-3-acetoxime | Drug Info | [23] | |||
| 8 | 7-bromoindirubin-3-oxime | Drug Info | [23] | |||
| 9 | 7-chloroindirubin-3-oxime | Drug Info | [23] | |||
| 10 | 7-fluoroindirubin-3-acetoxime | Drug Info | [23] | |||
| 11 | 7-fluoroindirubin-3-oxime | Drug Info | [23] | |||
| 12 | 7-iodoindirubin-3-oxime | Drug Info | [23] | |||
| 13 | BMS-739562 | Drug Info | [16] | |||
| 14 | BPR1K-0224 | Drug Info | [16] | |||
| 15 | Glycyl-H 1152 | Drug Info | [24] | |||
| 16 | Indirubin-3'-monoxime | Drug Info | [23] | |||
| 17 | Indirubin-3-acetoxime | Drug Info | [23] | |||
| 18 | Indirubin-3-methoxime | Drug Info | [23] | |||
| 19 | K00244 | Drug Info | [25] | |||
| 20 | MP-529 | Drug Info | [16] | |||
| 21 | PMID16451062C46 | Drug Info | [26] | |||
| 22 | PMID20855207C25 | Drug Info | [27] | |||
| 23 | quinazoline deriv. 1 | Drug Info | [28] | |||
| 24 | SU 6656 | Drug Info | [29] | |||
| 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 AURKC INCENP complex bound to VX-680 | PDB:6GR9 | ||||
| Method | X-ray diffraction | Resolution | 2.25 Å | Mutation | No | [30] |
| PDB Sequence |
RLVDDFEIGR
47 PLGKGKFGNV57 YLARLKESHF67 IVALKVLFKS77 QIEKEGLEHQ87 LRREIEIQAH 97 LQHPNILRLY107 NYFHDARRVY117 LILEYAPRGE127 LYKELQKSDK137 LDEQRTATII 147 EELADALTYC157 HDKKVIHRDI167 KPENLLLGFR177 GEVKIADFGW187 SVHTPSLRRK 197 MCGTLDYLPP208 EMIEGRTYDE218 KVDLWCIGVL228 CYELLVGYPP238 FESASHSETY 248 RRILKVDVRF258 PLSMPLGARD268 LISRLLRYQP278 LERLPLAQIL288 KHPWVQAHSR 298 RVLPPCA
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| Ligand Name: L-serine-O-phosphate | Ligand Info | |||||
| Structure Description | Human AURKC INCENP complex bound to BRD-7880 | PDB:6GR8 | ||||
| Method | X-ray diffraction | Resolution | 1.75 Å | Mutation | No | [31] |
| PDB Sequence |
GANSRRLVDD
42 FEIGRPLGKG52 KFGNVYLARL62 KESHFIVALK72 VLFKSQIEKE82 GLEHQLRREI 92 EIQAHLQHPN102 ILRLYNYFHD112 ARRVYLILEY122 APRGELYKEL132 QKSDKLDEQR 142 TATIIEELAD152 ALTYCHDKKV162 IHRDIKPENL172 LLGFRGEVKI182 ADFGWSVHTP 192 SLRRKMCGTL203 DYLPPEMIEG213 RTYDEKVDLW223 CIGVLCYELL233 VGYPPFESAS 243 HSETYRRILK253 VDVRFPLSMP263 LGARDLISRL273 LRYQPLERLP283 LAQILKHPWV 293 QAHSRRVLPP303
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| 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).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
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
Human Tissue Distribution
Biological Network Descriptors
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| Degree | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 1.82E-01 | Radiality | 1.30E+01 | Clustering coefficient | 1.00E+00 |
| Neighborhood connectivity | 3.45E+01 | Topological coefficient | 6.27E-01 | Eccentricity | 13 |
| 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 Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Oocyte meiosis | |||||
| Reactome | [+] 4 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 | |||||
| WikiPathways | [+] 5 WikiPathways | + | ||||
| 1 | EGF/EGFR Signaling Pathway | |||||
| 2 | JAK/STAT | |||||
| 3 | Gastric Cancer Network 1 | |||||
| 4 | Integrated Breast Cancer Pathway | |||||
| 5 | 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 | 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 2 | ClinicalTrials.gov (NCT02478320) Phase II Study of Ilorasertib (ABT348) in Patients With CDKN2A Deficient Solid Tumors. | |||||
| REF 3 | 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 4 | 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 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: 8060). | |||||
| REF 6 | 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 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: 8358). | |||||
| REF 8 | 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 9 | ClinicalTrials.gov (NCT01118611) Aurora B/C Kinase Inhibitor GSK1070916A in Treating Patients With Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 10 | ClinicalTrials.gov (NCT00939172) TTP607 in Refractory Solid Malignancies. U.S. National Institutes of Health. | |||||
| REF 11 | ClinicalTrials.gov (NCT00519662) Safety and Tolerability Study of SNS-314 for Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 12 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800024789) | |||||
| REF 13 | Potent and selective Aurora inhibitors identified by the expansion of a novel scaffold for protein kinase inhibition. J Med Chem. 2005 Apr 21;48(8):3080-4. | |||||
| REF 14 | Discovery of GSK1070916, a potent and selective inhibitor of Aurora B/C kinase. J Med Chem. 2010 May 27;53(10):3973-4001. | |||||
| REF 15 | 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 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. (Target id: 1936). | |||||
| REF 17 | 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 18 | 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 19 | Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2009 Jan-Feb;31(1):47-57. | |||||
| REF 20 | Water-soluble prodrugs of an Aurora kinase inhibitor. Bioorg Med Chem Lett. 2009 Mar 1;19(5):1409-12. | |||||
| REF 21 | Clinical experience with aurora kinase inhibitors: a review. Oncologist. 2009 Aug;14(8):780-93. | |||||
| REF 22 | Structural basis for the inhibition of Aurora A kinase by a novel class of high affinity disubstituted pyrimidine inhibitors. Bioorg Med Chem Lett. 2007 Feb 1;17(3):688-91. | |||||
| REF 23 | An integrated computational approach to the phenomenon of potent and selective inhibition of aurora kinases B and C by a series of 7-substituted in... J Med Chem. 2007 Aug 23;50(17):4027-37. | |||||
| REF 24 | Development of specific Rho-kinase inhibitors and their clinical application. Biochim Biophys Acta. 2005 Dec 30;1754(1-2):245-52. | |||||
| REF 25 | The discovery of the potent aurora inhibitor MK-0457 (VX-680). Bioorg Med Chem Lett. 2009 Jul 1;19(13):3586-92. | |||||
| REF 26 | Discovery of novel and potent thiazoloquinazolines as selective Aurora A and B kinase inhibitors. J Med Chem. 2006 Feb 9;49(3):955-70. | |||||
| REF 27 | Discovery of orally bioavailable imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors. Bioorg Med Chem Lett. 2010 Nov 15;20(22):6739-43. | |||||
| REF 28 | A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20523-8. | |||||
| REF 29 | The selectivity of protein kinase inhibitors: a further update. Biochem J. 2007 Dec 15;408(3):297-315. | |||||
| REF 30 | AURKC INCENP complex bound to BRD-7880 | |||||
| REF 31 | AURKC INCENP complex bound to BRD-7880 | |||||
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