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Aurora inhibitor - Wikipedia

From Wikipedia, the free encyclopedia

Aurora case study – six inhibitors and their action during cytokinesis

Aurora kinase inhibitors are a putative drug class for treating cancer. The Aurora kinase enzymes could be potential targets for novel small-molecule enzyme inhibitors.

Aurora kinases regulate cell cycle transit from G2 through cytokinesis, and thus are targets in cancer therapy.^[1] There are three mammalian aurora kinase genes, encoding aurora A, B and C. Intense investigation has focused on aurora A and B as they appear to play a role in oncogenesis^[2] with aurora A identified as a low penetrance tumor susceptibility gene in mice and humans.^[3]

Drug development

A new approach to inhibiting cancer growth that shows great promise for structure-based drug development is targeting enzymes central to cellular mitosis.^[4] Aurora kinases, so named because the scattered mitotic spindles generated by mutant forms resemble the Aurora Borealis, have gained a great deal of attention as possible anticancer drug targets.^[5]^[6] The Aurora enzymes are particularly significant because they are involved in a direct path to the nucleosome by phosphorylating histone H3.^[7]^[8] Furthermore, Aurora kinases are known to be oncogenic and overexpressed in various forms of cancerous growth, including leukemia, colon cancer, prostate cancer^[9] and breast cancer^[10] tumors.^[11]

So far three Aurora-kinase inhibitors have been described: ZM447439,^[12] hesperadin^[13]^[14] and VX-680. The last is in advanced stages (Phase II clinical trial) of a joint drug development by Vertex Pharmaceuticals's VX-680 (Sausville, 234, last posted on 12/18/06) and Merck & Co.,^[15] although the Phase II clinical trial was suspended in November, 2007 due to QT prolongation observed in one patient in Phase I trial.

Aurora structure

The structure and active site of Aurora-2-adenosine complex has been determined.^[16] The hinge (yellow), glycine-rich loop (blue), and activation loop (red) are key features of the protein kinase fold involved in binding adenosine. The protein backbone atoms of residues Glu-211, Ala-213 in the hinge region of Aurora-2, and the sidechain of residue Trp-277, located in the activation loop, bind adenosine through specific hydrogen bonds. There are no hydrogen bonds between the 2'-OH or 3'-OH groups of the ribose moiety and Aurora-2. Residues Lys-162 and Asp-274 are essential for Aurora-2 kinase activity but do not hydrogen bond to each other as seen in crystal structures of several other protein kinases.^{[citation needed]}

References

^ Andrews, Paul D.; Knatko, Elena; Moore, William J.; Swedlow, Jason R. (2003). "Mitotic mechanics: The auroras come into view". Current Opinion in Cell Biology. 15 (6): 672–683. doi:10.1016/j.ceb.2003.10.013. PMID 14644191.
^ Katayama, Hiroshi; Brinkley, W. R.; Sen, S. (2003). "The Aurora kinases: Role in cell transformation and tumorigenesis". Cancer and Metastasis Reviews. 22 (4): 451–464. doi:10.1023/a:1023789416385. PMID 12884918. S2CID 25350728.
^ Ewart-Toland, Amanda; Briassouli, Paraskevi; De Koning, John P.; Mao, Jian-Hua; Yuan, Jinwei; Chan, Florence; Maccarthy-Morrogh, Lucy; Ponder, Bruce A J.; Nagase, Hiroki; Burn, John; Ball, Sarah; Almeida, Maria; Linardopoulos, Spiros; Balmain, Allan (2003). "Identification of Stk6/STK15 as a candidate low-penetrance tumor-susceptibility gene in mouse and human". Nature Genetics. 34 (4): 403–412. doi:10.1038/ng1220. PMID 12881723. S2CID 29442841.
^ Nigg, Erich A. (2001). "Mitotic kinases as regulators of cell division and its checkpoints". Nature Reviews Molecular Cell Biology. 2 (1): 21–32. doi:10.1038/35048096. PMID 11413462. S2CID 205011994.
^ Keen, Nicholas; Taylor, Stephen (2004). "Aurora-kinase inhibitors as anticancer agents". Nature Reviews Cancer. 4 (12): 927–936. doi:10.1038/nrc1502. PMID 15573114. S2CID 28256419.
^ Carvajal, R. D.; Tse, A.; Schwartz, G. K. (2006). "Aurora Kinases: New Targets for Cancer Therapy". Clinical Cancer Research. 12 (23): 6869–6875. doi:10.1158/1078-0432.CCR-06-1405. PMID 17145803. S2CID 34256297.
^ Goto, Hidemasa; Yasui, Yoshihiro; Nigg, Erich A.; Inagaki, Masaki (2002). "Aurora-B phosphorylates Histone H3 at serine28 with regard to the mitotic chromosome condensation". Genes to Cells. 7 (1): 11–17. doi:10.1046/j.1356-9597.2001.00498.x. PMID 11856369.
^ Monier, K.; Mouradian, S.; Sullivan, K. F. (2006). "DNA methylation promotes Aurora-B-driven phosphorylation of histone H3 in chromosomal subdomains". Journal of Cell Science. 120 (Pt 1): 101–114. doi:10.1242/jcs.03326. PMID 17164288. S2CID 30767479.
^ Lee, Edmund Chun Yu; Frolov, Anna; Li, Rile; Ayala, Gustavo; Greenberg, Norman M. (2006). "Targeting Aurora Kinases for the Treatment of Prostate Cancer". Cancer Research. 66 (10): 4996–5002. doi:10.1158/0008-5472.CAN-05-2796. PMID 16707419.
^ Yang, Hua; Ou, Chien Chen; Feldman, Richard I.; Nicosia, Santo V.; Kruk, Patricia A.; Cheng, Jin Q. (2004). "Aurora-A Kinase Regulates Telomerase Activity through c-Myc in Human Ovarian and Breast Epithelial Cells". Cancer Research. 64 (2): 463–467. doi:10.1158/0008-5472.can-03-2907. PMID 14744757. S2CID 11727346.
^ Fu, J.; Bian, M.; Jiang, Q.; Zhang, C. (2007). "Roles of Aurora Kinases in Mitosis and Tumorigenesis". Molecular Cancer Research. 5 (1): 1–10. doi:10.1158/1541-7786.MCR-06-0208. PMID 17259342. S2CID 22233833.
^ Gadea, Bedrick B.; Ruderman, Joan V. (2005). "Aurora Kinase Inhibitor ZM447439 Blocks Chromosome-induced Spindle Assembly, the Completion of Chromosome Condensation, and the Establishment of the Spindle Integrity Checkpoint inXenopus Egg Extracts". Molecular Biology of the Cell. 16 (3): 1305–1318. doi:10.1091/mbc.e04-10-0891. PMC 551494. PMID 15616188.
^ Peters, Jan-Michael; Rieder, Conly L.; Van Meel, Jacques; Heckel, Armin; Walter, Rainer; Schnapp, Gisela; Zimmer, Christine; Laterra, Sabrina; Cole, Richard W.; Hauf, Silke (2003). "The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore–microtubule attachment and in maintaining the spindle assembly checkpoint". Journal of Cell Biology. 161 (2): 281–294. doi:10.1083/jcb.200208092. PMC 2172906. PMID 12707311.
^ Sakita-Suto, Shiho; Kanda, Akifumi; Suzuki, Fumio; Sato, Sunao; Takata, Takashi; Tatsuka, Masaaki (2007). "Aurora-B Regulates RNA Methyltransferase NSUN2". Molecular Biology of the Cell. 18 (3): 1107–1117. doi:10.1091/mbc.e06-11-1021. PMC 1805108. PMID 17215513.
^ Harrington, Elizabeth A.; Bebbington, David; Moore, Jeff; Rasmussen, Richele K.; Ajose-Adeogun, Abi O.; Nakayama, Tomoko; Graham, Joanne A.; Demur, Cecile; Hercend, Thierry; Diu-Hercend, Anita; Su, Michael; Golec, Julian M C.; Miller, Karen M. (2004). "VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo". Nature Medicine. 10 (3): 262–267. doi:10.1038/nm1003. PMID 14981513. S2CID 12918452.
^ Graham M. T. et al., Crystal Structure of Aurora-2, an Oncogenic Serine/Threonine Kinase J. Biol. Chem., (2002) 277: pp.42419-22

External links

Kinases: Serine/threonine-specific protein kinases (EC 2.7.11-12)

Serine/threonine-specific protein kinases (EC 2.7.11.1-EC 2.7.11.20)

Non-specific serine/threonine protein kinases (EC 2.7.11.1)	LATS1 LATS2 MAST1 MAST2 STK38 STK38L CIT ROCK1 SGK SGK2 SGK3 Protein kinase B AKT1 AKT2 AKT3 Ataxia telangiectasia mutated mTOR EIF-2 kinases PKR HRI EIF2AK3 EIF2AK4 Wee1 WEE1
Pyruvate dehydrogenase kinase (EC 2.7.11.2)	PDK1 PDK2 PDK3 PDK4
Dephospho-(reductase kinase) kinase (EC 2.7.11.3)	AMP-activated protein kinase α PRKAA1 PRKAA2 β PRKAB1 PRKAB2 γ PRKAG1 PRKAG2 PRKAG3
3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring) kinase (EC 2.7.11.4)	BCKDK BCKDHA BCKDHB
(isocitrate dehydrogenase (NADP+)) kinase (EC 2.7.11.5)	IDH2 IDH3A IDH3B IDH3G
(tyrosine 3-monooxygenase) kinase (EC 2.7.11.6)	STK4
Myosin-heavy-chain kinase (EC 2.7.11.7)	Aurora kinase Aurora A kinase Aurora B kinase Aurora C kinase
Fas-activated serine/threonine kinase (EC 2.7.11.8)	FASTK STK10
Goodpasture-antigen-binding protein kinase (EC 2.7.11.9)	-
IκB kinase (EC 2.7.11.10)	CHUK IKK2 TBK1 IKBKE IKBKG IKBKAP
cAMP-dependent protein kinase (EC 2.7.11.11)	Protein kinase A PRKACG PRKACB PRKACA PRKY
cGMP-dependent protein kinase (EC 2.7.11.12)	Protein kinase G PRKG1
Protein kinase C (EC 2.7.11.13)	Protein kinase C Protein kinase Cζ PKC alpha PRKCB1 PRKCD PRKCE PRKCH PRKCG PRKCI PRKCQ Protein kinase N1 PKN2 PKN3
Rhodopsin kinase (EC 2.7.11.14)	Rhodopsin kinase
Beta adrenergic receptor kinase (EC 2.7.11.15)	Beta adrenergic receptor kinase Beta adrenergic receptor kinase-2
G-protein coupled receptor kinases (EC 2.7.11.16)	GRK4 GRK5 GRK6
Ca2+/calmodulin-dependent (EC 2.7.11.17)	BRSK2 CAMK1 CAMK1A CAMK1B CAMK1D CAMK1G CAMK2 CAMK2A CAMK2B CAMK2D CAMK2G CAMK4 MLCK CASK CHEK1 CHEK2 DAPK1 DAPK2 DAPK3 STK11 MAPKAPK2 MAPKAPK3 MAPKAPK5 MARK1 MARK2 MARK3 MARK4 MELK MKNK1 MKNK2 NUAK1 NUAK2 OBSCN PASK PHKG1 PHKG2 PIM1 PIM2 PKD1 PRKD2 PRKD3 PSKH1 SNF1LK2 KIAA0999 STK40 SNF1LK SNRK SPEG TSSK2 Kalirin TRIB1 TRIB2 TRIB3 TRIO Titin DCLK1
Myosin light-chain kinase (EC 2.7.11.18)	MYLK MYLK2 MYLK3 MYLK4
Phosphorylase kinase (EC 2.7.11.19)	PHKA1 PHKA2 PHKB PHKG1 PHKG2
Elongation factor 2 kinase (EC 2.7.11.20)	EEF2K STK19
Polo kinase (EC 2.7.11.21)	PLK1 PLK2 PLK3 PLK4

Serine/threonine-specific protein kinases (EC 2.7.11.21-EC 2.7.11.30)

Polo kinase (EC 2.7.11.21)	PLK1 PLK2 PLK3 PLK4
Cyclin-dependent kinase (EC 2.7.11.22)	CDK1 CDK2 CDKL2 CDK3 CDK4 CDK5 CDKL5 CDK6 CDK7 CDK8 CDK9 CDK10 CDK12 CDC2L5 PCTK1 PCTK2 PCTK3 PFTK1 CDC2L1
(RNA-polymerase)-subunit kinase (EC 2.7.11.23)	RPS6KA5 RPS6KA4 P70S6 kinase P70-S6 Kinase 1 RPS6KB2 RPS6KA2 RPS6KA3 RPS6KA1 RPS6KC1
Mitogen-activated protein kinase (EC 2.7.11.24)	Extracellular signal-regulated MAPK1 MAPK3 MAPK4 MAPK6 MAPK7 MAPK12 MAPK15 C-Jun N-terminal MAPK8 MAPK9 MAPK10 P38 mitogen-activated protein MAPK11 MAPK13 MAPK14
MAP3K (EC 2.7.11.25)	MAP kinase kinase kinases MAP3K1 MAP3K2 MAP3K3 MAP3K4 MAP3K5 MAP3K6 MAP3K7 MAP3K8 RAFs ARAF BRAF KSR1 KSR2 MLKs MAP3K12 MAP3K13 MAP3K9 MAP3K10 MAP3K11 MAP3K7 ZAK CDC7 MAP3K14
Tau-protein kinase (EC 2.7.11.26)	TPK1 TTK GSK-3
(acetyl-CoA carboxylase) kinase (EC 2.7.11.27)	-
Tropomyosin kinase (EC 2.7.11.28)	-
Low-density-lipoprotein receptor kinase (EC 2.7.11.29)	-
Receptor protein serine/threonine kinase (EC 2.7.11.30)	Bone morphogenetic protein receptors BMPR1 BMPR1A BMPR1B BMPR2 ACVR1 ACVR1B ACVR1C ACVR2A ACVR2B ACVRL1 Anti-Müllerian hormone receptor

Dual-specificity kinases (EC 2.7.12)

MAP2K	MAP2K1 MAP2K2 MAP2K3 MAP2K4 MAP2K5 MAP2K6 MAP2K7

Transferases: phosphorus-containing groups (EC 2.7)

2.7.1-2.7.4:
phosphotransferase/kinase
(PO₄)

2.7.1: OH acceptor	Hexo- Gluco- Fructo- Hepatic Galacto- Phosphofructo- 1 Liver Muscle Platelet 2 Riboflavin Shikimate Thymidine ADP-thymidine NAD⁺ Glycerol Pantothenate Mevalonate Pyruvate Deoxycytidine PFP Diacylglycerol Phosphoinositide 3 Class I PI 3 Class II PI 3 Sphingosine Glucose-1,6-bisphosphate synthase
2.7.2: COOH acceptor	Phosphoglycerate Aspartate kinase
2.7.3: N acceptor	Creatine
2.7.4: PO₄ acceptor	Phosphomevalonate Adenylate Nucleoside-diphosphate Uridylate Guanylate Thiamine-diphosphate

2.7.6: diphosphotransferase
(P₂O₇)

2.7.7: nucleotidyltransferase
(PO₄-nucleoside)

Polymerase

DNA polymerase	DNA-directed DNA polymerase I/A γ θ ν T7 Taq II/B α δ ε ζ Pfu III/C IV/X β λ μ TDT V/Y η ι κ RNA-directed DNA polymerase Reverse transcriptase Telomerase
RNA polymerase	Template-directed RNA polymerase I II III IV V ssRNAP POLRMT Primase 1 2 PrimPol RNA-dependent RNA polymerase Polyadenylation PAP PNPase

Phosphorolytic
3' to 5' exoribonuclease

Nucleotidyltransferase

Guanylyltransferase

mRNA capping enzyme

Other

2.7.8: miscellaneous

Phosphatidyltransferases	CDP-diacylglycerol—glycerol-3-phosphate 3-phosphatidyltransferase CDP-diacylglycerol—serine O-phosphatidyltransferase CDP-diacylglycerol—inositol 3-phosphatidyltransferase CDP-diacylglycerol—choline O-phosphatidyltransferase
Glycosyl-1-phosphotransferase	N-acetylglucosamine-1-phosphate transferase

2.7.10-2.7.13: protein kinase
(PO₄; protein acceptor)

2.7.10: protein-tyrosine	see tyrosine kinases
2.7.11: protein-serine/threonine	see serine/threonine-specific protein kinases
2.7.12: protein-dual-specificity	see serine/threonine-specific protein kinases
2.7.13: protein-histidine	Protein-histidine pros-kinase Protein-histidine tele-kinase Histidine kinase

v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)

Categories:

Hidden categories:

Drug development

Aurora structure

See also

References

External links