Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTLYXIT)

• DTT Name: Aurora kinase C (AURKC)
• 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
• Gene Name: AURKC
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: AURKC_HUMAN
• TTD ID: T97592
• EC Number: EC 2.7.11.1
• Sequence:
  MSSPRAVVQLGKAQPAGEELATANQTAQQPSSPAMRRLTVDDFEIGRPLGKGKFGNVYLA
  RLKESHFIVALKVLFKSQIEKEGLEHQLRREIEIQAHLQHPNILRLYNYFHDARRVYLIL
  EYAPRGELYKELQKSEKLDEQRTATIIEELADALTYCHDKKVIHRDIKPENLLLGFRGEV
  KIADFGWSVHTPSLRRKTMCGTLDYLPPEMIEGRTYDEKVDLWCIGVLCYELLVGYPPFE
  SASHSETYRRILKVDVRFPLSMPLGARDLISRLLRYQPLERLPLAQILKHPWVQAHSRRV
  LPPCAQMAS
• 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.
• KEGG Pathway: Oocyte meiosis (hsa04114)
• Reactome Pathway:
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  RHO GTPases Activate Formins (R-HSA-5663220)
  APC/C (R-HSA-174178)

Molecular Interaction Atlas (MIA) of This DTT

7 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ABT-348	DMMZOYN	Haematological malignancy	2B33.Y	Phase 2	[1]
PHA-739358	DMGYBZI	Prostate cancer	2C82.0	Phase 2	[2]
AMG 900	DMASGXJ	Solid tumour/cancer	2A00-2F9Z	Phase 1	[3]
GSK1070916	DMXRPT6	Advanced solid tumour	2A00-2F9Z	Phase 1	[4]
GSK1070916A	DMCJUI9	Solid tumour/cancer	2A00-2F9Z	Phase 1	[4]
HPP-607	DM5VSZR	Solid tumour/cancer	2A00-2F9Z	Phase 1	[5]
SNS-314	DMAC5F2	Solid tumour/cancer	2A00-2F9Z	Phase 1	[6]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
MK-6592	DMB5NOI	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 1	[7]

20 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2np8	DMRXDS2	Discovery agent	N.A.	Investigative	[8]
6-bromoindirubin-3-oxime	DM12WYV	Discovery agent	N.A.	Investigative	[9]
7-bromoindirubin-3-acetoxime	DM3G8I7	Discovery agent	N.A.	Investigative	[9]
7-bromoindirubin-3-oxime	DM07QD3	Discovery agent	N.A.	Investigative	[9]
7-chloroindirubin-3-oxime	DM28NAB	Discovery agent	N.A.	Investigative	[9]
7-fluoroindirubin-3-acetoxime	DM70I3V	Discovery agent	N.A.	Investigative	[9]
7-fluoroindirubin-3-oxime	DMQD34N	Discovery agent	N.A.	Investigative	[9]
7-iodoindirubin-3-oxime	DMNFI02	Discovery agent	N.A.	Investigative	[9]
BMS-739562	DMFODQV	Solid tumour/cancer	2A00-2F9Z	Investigative	[5]
BPR1K-0224	DMJPN8Z	Solid tumour/cancer	2A00-2F9Z	Investigative	[5]
Glycyl-H 1152	DM0SCK8	Discovery agent	N.A.	Investigative	[10]
Indirubin-3'-monoxime	DMLRQH0	Discovery agent	N.A.	Investigative	[9]
Indirubin-3-acetoxime	DM3UR1E	Discovery agent	N.A.	Investigative	[9]
Indirubin-3-methoxime	DMZ5ODC	Discovery agent	N.A.	Investigative	[9]
K00244	DM2BKU8	Discovery agent	N.A.	Investigative	[11]
MP-529	DMV5T1I	Solid tumour/cancer	2A00-2F9Z	Investigative	[5]
PMID16451062C46	DMT3RUE	Discovery agent	N.A.	Investigative	[12]
PMID20855207C25	DMNEB6J	Discovery agent	N.A.	Investigative	[13]
quinazoline deriv. 1	DMJDU5S	Discovery agent	N.A.	Investigative	[14]
SU 6656	DMF1P6W	Discovery agent	N.A.	Investigative	[15]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Prostate cancer	2C82	Prostate	2.66E-02	-0.53	-0.8

References

• [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.
• [2] 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.
• [3] 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.
• [4] Discovery of GSK1070916, a potent and selective inhibitor of Aurora B/C kinase. J Med Chem. 2010 May 27;53(10):3973-4001.
• [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. (Target id: 1936).
• [6] 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.
• [7] Clinical experience with aurora kinase inhibitors: a review. Oncologist. 2009 Aug;14(8):780-93.
• [8] 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.
• [9] 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.
• [10] Development of specific Rho-kinase inhibitors and their clinical application. Biochim Biophys Acta. 2005 Dec 30;1754(1-2):245-52.
• [11] The discovery of the potent aurora inhibitor MK-0457 (VX-680). Bioorg Med Chem Lett. 2009 Jul 1;19(13):3586-92.
• [12] Discovery of novel and potent thiazoloquinazolines as selective Aurora A and B kinase inhibitors. J Med Chem. 2006 Feb 9;49(3):955-70.
• [13] Discovery of orally bioavailable imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors. Bioorg Med Chem Lett. 2010 Nov 15;20(22):6739-43.
• [14] 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.
• [15] The selectivity of protein kinase inhibitors: a further update. Biochem J. 2007 Dec 15;408(3):297-315.