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==Complex of Aurora-A bound to an Imidazopyridine-based inhibitor==
==Complex of Aurora-A bound to an Imidazopyridine-based inhibitor==
<StructureSection load='4b0g' size='340' side='right' caption='[[4b0g]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
<StructureSection load='4b0g' size='340' side='right'caption='[[4b0g]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4b0g]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4B0G OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4B0G FirstGlance]. <br>
<table><tr><td colspan='2'>[[4b0g]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4B0G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4B0G FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=VEK:6-BROMO-2-(1-METHYL-1H-IMIDAZOL-5-YL)-7-{4-[(5-METHYL-1,2-OXAZOL-3-YL)METHYL]PIPERAZIN-1-YL}-1H-IMIDAZO[4,5-B]PYRIDINE'>VEK</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1mq4|1mq4]], [[1muo|1muo]], [[1ol5|1ol5]], [[1ol6|1ol6]], [[1ol7|1ol7]], [[2bmc|2bmc]], [[2c6d|2c6d]], [[2c6e|2c6e]], [[2j4z|2j4z]], [[2j50|2j50]], [[2w1c|2w1c]], [[2w1d|2w1d]], [[2w1e|2w1e]], [[2w1f|2w1f]], [[2w1g|2w1g]], [[2wqe|2wqe]], [[2wtv|2wtv]], [[2wtw|2wtw]], [[2x6d|2x6d]], [[2x6e|2x6e]], [[2x81|2x81]], [[2xne|2xne]], [[2xng|2xng]], [[2xru|2xru]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=VEK:6-BROMO-2-(1-METHYL-1H-IMIDAZOL-5-YL)-7-{4-[(5-METHYL-1,2-OXAZOL-3-YL)METHYL]PIPERAZIN-1-YL}-1H-IMIDAZO[4,5-B]PYRIDINE'>VEK</scene></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4b0g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b0g OCA], [https://pdbe.org/4b0g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4b0g RCSB], [https://www.ebi.ac.uk/pdbsum/4b0g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4b0g ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4b0g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b0g OCA], [http://pdbe.org/4b0g PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4b0g RCSB], [http://www.ebi.ac.uk/pdbsum/4b0g PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4b0g ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/AURKA_HUMAN AURKA_HUMAN]] Mitotic serine/threonine kinases that contributes to the regulation of cell cycle progression. 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 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.<ref>PMID:9606188</ref> <ref>PMID:11039908</ref> <ref>PMID:11551964</ref> <ref>PMID:12390251</ref> <ref>PMID:13678582</ref> <ref>PMID:14523000</ref> <ref>PMID:15147269</ref> <ref>PMID:14990569</ref> <ref>PMID:15128871</ref> <ref>PMID:14702041</ref> <ref>PMID:15987997</ref> <ref>PMID:18056443</ref> <ref>PMID:17604723</ref> <ref>PMID:17360485</ref> <ref>PMID:18615013</ref> <ref>PMID:19812038</ref> <ref>PMID:19351716</ref> <ref>PMID:19668197</ref> <ref>PMID:19357306</ref> <ref>PMID:20643351</ref> <ref>PMID:17125279</ref>
[https://www.uniprot.org/uniprot/AURKA_HUMAN AURKA_HUMAN] Mitotic serine/threonine kinases that contributes to the regulation of cell cycle progression. 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 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.<ref>PMID:9606188</ref> <ref>PMID:11039908</ref> <ref>PMID:11551964</ref> <ref>PMID:12390251</ref> <ref>PMID:13678582</ref> <ref>PMID:14523000</ref> <ref>PMID:15147269</ref> <ref>PMID:14990569</ref> <ref>PMID:15128871</ref> <ref>PMID:14702041</ref> <ref>PMID:15987997</ref> <ref>PMID:18056443</ref> <ref>PMID:17604723</ref> <ref>PMID:17360485</ref> <ref>PMID:18615013</ref> <ref>PMID:19812038</ref> <ref>PMID:19351716</ref> <ref>PMID:19668197</ref> <ref>PMID:19357306</ref> <ref>PMID:20643351</ref> <ref>PMID:17125279</ref>  
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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==See Also==
==See Also==
*[[Serine/threonine protein kinase|Serine/threonine protein kinase]]
*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Non-specific serine/threonine protein kinase]]
[[Category: Large Structures]]
[[Category: Bayliss, R]]
[[Category: Bayliss R]]
[[Category: Kosmopoulou, M]]
[[Category: Kosmopoulou M]]
[[Category: Mitosis]]
[[Category: Transferase]]

Latest revision as of 14:40, 20 December 2023

Complex of Aurora-A bound to an Imidazopyridine-based inhibitorComplex of Aurora-A bound to an Imidazopyridine-based inhibitor

Structural highlights

4b0g is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.5Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

AURKA_HUMAN Mitotic serine/threonine kinases that contributes to the regulation of cell cycle progression. 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 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.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21]

Publication Abstract from PubMed

Optimization of the imidazo[4,5-b]pyridine-based series of Aurora kinase inhibitors led to the identification of 6-chloro-7-(4-(4-chlorobenzyl)piperazin-1-yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H -imidazo[4,5-b]pyridine (27e), a potent inhibitor of Aurora kinases (Aurora-A K(d) = 7.5 nM, Aurora-B K(d) = 48 nM), FLT3 kinase (K(d) = 6.2 nM), and FLT3 mutants including FLT3-ITD (K(d) = 38 nM) and FLT3(D835Y) (K(d) = 14 nM). FLT3-ITD causes constitutive FLT3 kinase activation and is detected in 20-35% of adults and 15% of children with acute myeloid leukemia (AML), conferring a poor prognosis in both age groups. In an in vivo setting, 27e strongly inhibited the growth of a FLT3-ITD-positive AML human tumor xenograft (MV4-11) following oral administration, with in vivo biomarker modulation and plasma free drug exposures consistent with dual FLT3 and Aurora kinase inhibition. Compound 27e, an orally bioavailable dual FLT3 and Aurora kinase inhibitor, was selected as a preclinical development candidate for the treatment of human malignancies, in particular AML, in adults and children.

Optimization of imidazo[4,5-b]pyridine-based kinase inhibitors: identification of a dual FLT3/Aurora kinase inhibitor as an orally bioavailable preclinical development candidate for the treatment of acute myeloid leukemia.,Bavetsias V, Crumpler S, Sun C, Avery S, Atrash B, Faisal A, Moore AS, Kosmopoulou M, Brown N, Sheldrake PW, Bush K, Henley A, Box G, Valenti M, de Haven Brandon A, Raynaud FI, Workman P, Eccles SA, Bayliss R, Linardopoulos S, Blagg J J Med Chem. 2012 Oct 25;55(20):8721-34. doi: 10.1021/jm300952s. Epub 2012 Oct 8. PMID:23043539[22]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Bischoff JR, Anderson L, Zhu Y, Mossie K, Ng L, Souza B, Schryver B, Flanagan P, Clairvoyant F, Ginther C, Chan CS, Novotny M, Slamon DJ, Plowman GD. A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J. 1998 Jun 1;17(11):3052-65. PMID:9606188 doi:10.1093/emboj/17.11.3052
  2. ↑ Walter AO, Seghezzi W, Korver W, Sheung J, Lees E. The mitotic serine/threonine kinase Aurora2/AIK is regulated by phosphorylation and degradation. Oncogene. 2000 Oct 5;19(42):4906-16. PMID:11039908 doi:10.1038/sj.onc.1203847
  3. ↑ Katayama H, Zhou H, Li Q, Tatsuka M, Sen S. Interaction and feedback regulation between STK15/BTAK/Aurora-A kinase and protein phosphatase 1 through mitotic cell division cycle. J Biol Chem. 2001 Dec 7;276(49):46219-24. Epub 2001 Sep 10. PMID:11551964 doi:10.1074/jbc.M107540200
  4. ↑ Marumoto T, Hirota T, Morisaki T, Kunitoku N, Zhang D, Ichikawa Y, Sasayama T, Kuninaka S, Mimori T, Tamaki N, Kimura M, Okano Y, Saya H. Roles of aurora-A kinase in mitotic entry and G2 checkpoint in mammalian cells. Genes Cells. 2002 Nov;7(11):1173-82. PMID:12390251
  5. ↑ Hirota T, Kunitoku N, Sasayama T, Marumoto T, Zhang D, Nitta M, Hatakeyama K, Saya H. Aurora-A and an interacting activator, the LIM protein Ajuba, are required for mitotic commitment in human cells. Cell. 2003 Sep 5;114(5):585-98. PMID:13678582
  6. ↑ Marumoto T, Honda S, Hara T, Nitta M, Hirota T, Kohmura E, Saya H. Aurora-A kinase maintains the fidelity of early and late mitotic events in HeLa cells. J Biol Chem. 2003 Dec 19;278(51):51786-95. Epub 2003 Oct 1. PMID:14523000 doi:10.1074/jbc.M306275200
  7. ↑ Toji S, Yabuta N, Hosomi T, Nishihara S, Kobayashi T, Suzuki S, Tamai K, Nojima H. The centrosomal protein Lats2 is a phosphorylation target of Aurora-A kinase. Genes Cells. 2004 May;9(5):383-97. PMID:15147269 doi:10.1111/j.1356-9597.2004.00732.x
  8. ↑ Ouchi M, Fujiuchi N, Sasai K, Katayama H, Minamishima YA, Ongusaha PP, Deng C, Sen S, Lee SW, Ouchi T. BRCA1 phosphorylation by Aurora-A in the regulation of G2 to M transition. J Biol Chem. 2004 May 7;279(19):19643-8. Epub 2004 Feb 27. PMID:14990569 doi:10.1074/jbc.M311780200
  9. ↑ Dutertre S, Cazales M, Quaranta M, Froment C, Trabut V, Dozier C, Mirey G, Bouche JP, Theis-Febvre N, Schmitt E, Monsarrat B, Prigent C, Ducommun B. Phosphorylation of CDC25B by Aurora-A at the centrosome contributes to the G2-M transition. J Cell Sci. 2004 May 15;117(Pt 12):2523-31. Epub 2004 May 5. PMID:15128871 doi:10.1242/jcs.01108
  10. ↑ Katayama H, Sasai K, Kawai H, Yuan ZM, Bondaruk J, Suzuki F, Fujii S, Arlinghaus RB, Czerniak BA, Sen S. Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53. Nat Genet. 2004 Jan;36(1):55-62. Epub 2003 Dec 14. PMID:14702041 doi:10.1038/ng1279
  11. ↑ Yu CT, Hsu JM, Lee YC, Tsou AP, Chou CK, Huang CY. Phosphorylation and stabilization of HURP by Aurora-A: implication of HURP as a transforming target of Aurora-A. Mol Cell Biol. 2005 Jul;25(14):5789-800. PMID:15987997 doi:10.1128/MCB.25.14.5789-5800.2005
  12. ↑ Sankaran S, Crone DE, Palazzo RE, Parvin JD. Aurora-A kinase regulates breast cancer associated gene 1 inhibition of centrosome-dependent microtubule nucleation. Cancer Res. 2007 Dec 1;67(23):11186-94. PMID:18056443 doi:10.1158/0008-5472.CAN-07-2578
  13. ↑ Pugacheva EN, Jablonski SA, Hartman TR, Henske EP, Golemis EA. HEF1-dependent Aurora A activation induces disassembly of the primary cilium. Cell. 2007 Jun 29;129(7):1351-63. PMID:17604723 doi:10.1016/j.cell.2007.04.035
  14. ↑ Manfredi MG, Ecsedy JA, Meetze KA, Balani SK, Burenkova O, Chen W, Galvin KM, Hoar KM, Huck JJ, LeRoy PJ, Ray ET, Sells TB, Stringer B, Stroud SG, Vos TJ, Weatherhead GS, Wysong DR, Zhang M, Bolen JB, Claiborne CF. Antitumor activity of MLN8054, an orally active small-molecule inhibitor of Aurora A kinase. Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4106-11. Epub 2007 Feb 23. PMID:17360485 doi:10.1073/pnas.0608798104
  15. ↑ Macurek L, Lindqvist A, Lim D, Lampson MA, Klompmaker R, Freire R, Clouin C, Taylor SS, Yaffe MB, Medema RH. Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery. Nature. 2008 Sep 4;455(7209):119-23. doi: 10.1038/nature07185. Epub 2008 Jul 9. PMID:18615013 doi:10.1038/nature07185
  16. ↑ Khazaei MR, Puschel AW. Phosphorylation of the par polarity complex protein Par3 at serine 962 is mediated by aurora a and regulates its function in neuronal polarity. J Biol Chem. 2009 Nov 27;284(48):33571-9. doi: 10.1074/jbc.M109.055897. Epub 2009, Oct 6. PMID:19812038 doi:10.1074/jbc.M109.055897
  17. ↑ Jang CY, Coppinger JA, Seki A, Yates JR 3rd, Fang G. Plk1 and Aurora A regulate the depolymerase activity and the cellular localization of Kif2a. J Cell Sci. 2009 May 1;122(Pt 9):1334-41. doi: 10.1242/jcs.044321. Epub 2009 Apr , 7. PMID:19351716 doi:10.1242/jcs.044321
  18. ↑ Mori D, Yamada M, Mimori-Kiyosue Y, Shirai Y, Suzuki A, Ohno S, Saya H, Wynshaw-Boris A, Hirotsune S. An essential role of the aPKC-Aurora A-NDEL1 pathway in neurite elongation by modulation of microtubule dynamics. Nat Cell Biol. 2009 Sep;11(9):1057-68. Epub 2009 Aug 9. PMID:19668197 doi:ncb1919
  19. ↑ Fu J, Bian M, Liu J, Jiang Q, Zhang C. A single amino acid change converts Aurora-A into Aurora-B-like kinase in terms of partner specificity and cellular function. Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):6939-44. doi:, 10.1073/pnas.0900833106. Epub 2009 Apr 8. PMID:19357306 doi:10.1073/pnas.0900833106
  20. ↑ Kinzel D, Boldt K, Davis EE, Burtscher I, Trumbach D, Diplas B, Attie-Bitach T, Wurst W, Katsanis N, Ueffing M, Lickert H. Pitchfork regulates primary cilia disassembly and left-right asymmetry. Dev Cell. 2010 Jul 20;19(1):66-77. doi: 10.1016/j.devcel.2010.06.005. PMID:20643351 doi:10.1016/j.devcel.2010.06.005
  21. ↑ Fancelli D, Moll J, Varasi M, Bravo R, Artico R, Berta D, Bindi S, Cameron A, Candiani I, Cappella P, Carpinelli P, Croci W, Forte B, Giorgini ML, Klapwijk J, Marsiglio A, Pesenti E, Rocchetti M, Roletto F, Severino D, Soncini C, Storici P, Tonani R, Zugnoni P, Vianello P. 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles: identification of a potent Aurora kinase inhibitor with a favorable antitumor kinase inhibition profile. J Med Chem. 2006 Nov 30;49(24):7247-51. PMID:17125279 doi:10.1021/jm060897w
  22. ↑ Bavetsias V, Crumpler S, Sun C, Avery S, Atrash B, Faisal A, Moore AS, Kosmopoulou M, Brown N, Sheldrake PW, Bush K, Henley A, Box G, Valenti M, de Haven Brandon A, Raynaud FI, Workman P, Eccles SA, Bayliss R, Linardopoulos S, Blagg J. Optimization of imidazo[4,5-b]pyridine-based kinase inhibitors: identification of a dual FLT3/Aurora kinase inhibitor as an orally bioavailable preclinical development candidate for the treatment of acute myeloid leukemia. J Med Chem. 2012 Oct 25;55(20):8721-34. doi: 10.1021/jm300952s. Epub 2012 Oct 8. PMID:23043539 doi:http://dx.doi.org/10.1021/jm300952s

4b0g, resolution 2.50Å

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