Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT5LS6T)

• DTT Name: Aurora kinase B (AURKB)
• 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
• Gene Name: AURKB
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: AURKB_HUMAN
• TTD ID: T46781
• EC Number: EC 2.7.11.1
• Sequence:
  MAQKENSYPWPYGRQTAPSGLSTLPQRVLRKEPVTPSALVLMSRSNVQPTAAPGQKVMEN
  SSGTPDILTRHFTIDDFEIGRPLGKGKFGNVYLAREKKSHFIVALKVLFKSQIEKEGVEH
  QLRREIEIQAHLHHPNILRLYNYFYDRRRIYLILEYAPRGELYKELQKSCTFDEQRTATI
  MEELADALMYCHGKKVIHRDIKPENLLLGLKGELKIADFGWSVHAPSLRRKTMCGTLDYL
  PPEMIEGRMHNEKVDLWCIGVLCYELLVGNPPFESASHNETYRRIVKVDLKFPASVPMGA
  QDLISKLLRHNPSERLPLAQVSAHPWVRANSRRVLPPSALQSVA
• 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.
• Reactome Pathway:
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  RHO GTPases Activate Formins (R-HSA-5663220)
  Mitotic Prometaphase (R-HSA-68877)
  APC/C (R-HSA-174178)

Molecular Interaction Atlas (MIA) of This DTT

17 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	[1]
ABT-348	DMMZOYN	Haematological malignancy	2B33.Y	Phase 2	[2]
PHA-739358	DMGYBZI	Prostate cancer	2C82.0	Phase 2	[3]
VX-680	DM93YKJ	Solid tumour/cancer	2A00-2F9Z	Phase 2	[4]
AMG 900	DMASGXJ	Solid tumour/cancer	2A00-2F9Z	Phase 1	[5]
AZD-1152-HQPA	DMMW72C	Solid tumour/cancer	2A00-2F9Z	Phase 1	[6]
BI-811283	DMNUY32	Acute myeloid leukaemia	2A60	Phase 1	[7]
BI-831266	DMOJZUE	Solid tumour/cancer	2A00-2F9Z	Phase 1	[8]
BI-847325	DMY4B6J	Solid tumour/cancer	2A00-2F9Z	Phase 1	[9]
CYC116	DMUMHXT	Solid tumour/cancer	2A00-2F9Z	Phase 1	[10]
GSK1070916	DMXRPT6	Advanced solid tumour	2A00-2F9Z	Phase 1	[11]
GSK1070916A	DMCJUI9	Solid tumour/cancer	2A00-2F9Z	Phase 1	[11]
HPP-607	DM5VSZR	Solid tumour/cancer	2A00-2F9Z	Phase 1	[12]
MK-5108	DMFGYKS	Solid tumour/cancer	2A00-2F9Z	Phase 1	[13]
R763	DME0CJ9	Haematological malignancy	2B33.Y	Phase 1	[14]
SNS-314	DMAC5F2	Solid tumour/cancer	2A00-2F9Z	Phase 1	[15]
TAK-901	DM5KDGI	Haematological malignancy	2B33.Y	Phase 1	[16]

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	[3]

1 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Deguelin	DMXT7WG	Esophageal squamous cell carcinoma	2E60.1	Investigative	[17]

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	3.52E-36	-0.82	-1.62
Prostate cancer	2C82	Prostate	3.85E-05	0.2	0.86

References

• [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.
• [2] 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.
• [3] Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Aurora kinase inhibitors: progress towards the clinic. Invest New Drugs. 2012 Dec;30(6):2411-32.
• [8] 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.
• [9] doi: 10.1158/1535-7163.TARG-13-B281
• [10] Clinical pipeline report, company report or official report of Cyclacel.
• [11] Discovery of GSK1070916, a potent and selective inhibitor of Aurora B/C kinase. J Med Chem. 2010 May 27;53(10):3973-4001.
• [12] 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).
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Clinical pipeline report, company report or official report of Takeda (2009).
• [17] An Electrophilic Deguelin Analogue Inhibits STAT3 Signaling in H- Ras-Transformed Human Mammary Epithelial Cells: The Cysteine 259 Residue as a Potential Target. Biomedicines. 2020 Oct 12;8(10):407.