Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTPS3C0)

• DTT Name: Aurora kinase A (AURKA)
• Synonyms: hARK1; Serine/threonine-protein kinase aurora-A; Serine/threonine-protein kinase 6; Serine/threonine-protein kinase 15; Serine/threonine kinase 15; STK6; STK15; IAK1; Breast tumor-amplified kinase; BTAK; Aurora/IPL1-related kinase 1; Aurora-related kinase 1; Aurora-A; Aurora 2; AYK1; AURA; ARK1; ARK-1; AIRK1; AIK
• Gene Name: AURKA
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: AURKA_HUMAN
• TTD ID: T87675
• EC Number: EC 2.7.11.1
• Sequence:
  MDRSKENCISGPVKATAPVGGPKRVLVTQQFPCQNPLPVNSGQAQRVLCPSNSSQRVPLQ
  AQKLVSSHKPVQNQKQKQLQATSVPHPVSRPLNNTQKSKQPLPSAPENNPEEELASKQKN
  EESKKRQWALEDFEIGRPLGKGKFGNVYLAREKQSKFILALKVLFKAQLEKAGVEHQLRR
  EVEIQSHLRHPNILRLYGYFHDATRVYLILEYAPLGTVYRELQKLSKFDEQRTATYITEL
  ANALSYCHSKRVIHRDIKPENLLLGSAGELKIADFGWSVHAPSSRRTTLCGTLDYLPPEM
  IEGRMHDEKVDLWSLGVLCYEFLVGKPPFEANTYQETYKRISRVEFTFPDFVTEGARDLI
  SRLLKHNPSQRPMLREVLEHPWITANSSKPSNCQNKESASKQS
• Function: Associates with the centrosome and the spindle microtubules during mitosis and plays a critical role in various mitotic events including the establishment of mitotic spindle, centrosome duplication, centrosome separation as well as maturation, chromosomal alignment, spindle assembly checkpoint, and cytokinesis. Required for normal spindle positioning during mitosis and for the localization of NUMA1 and DCTN1 to the cell cortex during metaphase. Required for initial activation of CDK1 at centrosomes. Phosphorylates numerous target proteins, including ARHGEF2, BORA, BRCA1, CDC25B, DLGP5, HDAC6, KIF2A, LATS2, NDEL1, PARD3, PPP1R2, PLK1, RASSF1, TACC3, p53/TP53 and TPX2. Regulates KIF2A tubulin depolymerase activity. Required for normal axon formation. Plays a role in microtubule remodeling during neurite extension. Important for microtubule formation and/or stabilization. Also acts as a key regulatory component of the p53/TP53 pathway, and particularly the checkpoint-response pathways critical for oncogenic transformation of cells, by phosphorylating and stabilizing p53/TP53. Phosphorylates its own inhibitors, the protein phosphatase type 1 (PP1) isoforms, to inhibit their activity. Necessary for proper cilia disassembly prior to mitosis. Mitotic serine/threonine kinase that contributes to the regulation of cell cycle progression.
• KEGG Pathway: Oocyte meiosis (hsa04114)
• Reactome Pathway:
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)
  APC/C (R-HSA-174178)

Molecular Interaction Atlas (MIA) of This DTT

16 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AT9283	DMQ94CT	Solid tumour/cancer	2A00-2F9Z	Phase 3	[2]
MLN8237	DMO8PT9	Solid tumour/cancer	2A00-2F9Z	Phase 3	[1]
ABT-348	DMMZOYN	Haematological malignancy	2B33.Y	Phase 2	[3]
ENMD-2076	DMJZVPB	Acute myeloid leukaemia	2A60	Phase 2	[4]
PHA-739358	DMGYBZI	Prostate cancer	2C82.0	Phase 2	[4]
VX-680	DM93YKJ	Solid tumour/cancer	2A00-2F9Z	Phase 2	[5]
LY3295668	DM8RJTB	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[6]
AMG 900	DMASGXJ	Solid tumour/cancer	2A00-2F9Z	Phase 1	[7]
CYC116	DMUMHXT	Solid tumour/cancer	2A00-2F9Z	Phase 1	[8]
HPP-607	DM5VSZR	Solid tumour/cancer	2A00-2F9Z	Phase 1	[9]
MK-5108	DMFGYKS	Solid tumour/cancer	2A00-2F9Z	Phase 1	[10]
MLN8054	DMUANF3	Solid tumour/cancer	2A00-2F9Z	Phase 1	[5]
R763	DME0CJ9	Haematological malignancy	2B33.Y	Phase 1	[11]
SNS-314	DMAC5F2	Solid tumour/cancer	2A00-2F9Z	Phase 1	[12]
TAS-119	DMJXBVP	Solid tumour/cancer	2A00-2F9Z	Phase 1	[13]
VIC-1911	DMDFC2Y	Solid tumour/cancer	2A00-2F9Z	Phase 1	[14]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PF-03814735	DMO4S6T	Advanced solid tumour	2A00-2F9Z	Discontinued in Phase 1	[4]

9 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2-(1H-pyrazol-3-yl)-1H-benzimidazole	DMHSORL	Discovery agent	N.A.	Investigative	[15]
4-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine	DM9MPHF	Discovery agent	N.A.	Investigative	[16]
6-bromoindirubin-3-oxime	DM12WYV	Discovery agent	N.A.	Investigative	[17]
7-fluoroindirubin-3-oxime	DMQD34N	Discovery agent	N.A.	Investigative	[17]
Indirubin-3'-monoxime	DMLRQH0	Discovery agent	N.A.	Investigative	[17]
Indirubin-3-acetoxime	DM3UR1E	Discovery agent	N.A.	Investigative	[17]
Indirubin-3-methoxime	DMZ5ODC	Discovery agent	N.A.	Investigative	[17]
Phosphonothreonine	DMTFHPI	Discovery agent	N.A.	Investigative	[18]
ZM-447439	DMFP8WE	Discovery agent	N.A.	Investigative	[19]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Acute myelocytic leukaemia	2C82	Bone marrow	9.41E-46	-1.78	-2.05
Prostate cancer	2C82	Prostate	6.68E-08	1.47	1.84

References

• [1] Effect of Aurora A kinase inhibitor MLN8237 combined with rituximab on antitumor activity in preclinical B-cell non-Hodgkin's lymphoma models. Journal of Clinical Oncology, 2009:8553.
• [2] 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.
• [3] 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.
• [4] Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
• [5] 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.
• [6] Aurora A-Selective Inhibitor LY3295668 Leads to Dominant Mitotic Arrest, Apoptosis in Cancer Cells, and Shows Potent Preclinical Antitumor Efficacy. Mol Cancer Ther. 2019 Dec;18(12):2207-2219.
• [7] 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.
• [8] Clinical pipeline report, company report or official report of Cyclacel.
• [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. (Target id: 1936).
• [10] 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.
• [11] 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.
• [12] 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.
• [13] TAS-119, a selective Aurora A inhibitor, enhanced the antitumor efficacy of taxanes in multiple human tumor cell lines including paclitaxel-resistant cells. Molecular Cancer Therapeutics. 01/2014; 12(11_Supplement):A268-A268.
• [14] Clinical pipeline report, company report or official report of VITRAC Therapeutics.
• [15] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [16] Discovery of a new series of Aurora inhibitors through truncation of GSK1070916. Bioorg Med Chem Lett. 2010 Apr 15;20(8):2552-5.
• [17] 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.
• [18] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [19] Accurate prediction of the relative potencies of members of a series of kinase inhibitors using molecular docking and MM-GBSA scoring. J Med Chem. 2006 Aug 10;49(16):4805-8.