Specific small-molecule activator of Aurora kinase A induces autophosphorylation in a cell-free systems

被引：41

作者：

Kishore, A. Hari ^{[1
]}

Vedamurthy, B. M. ^{[2
]}

Mantelingu, K. ^{[2
]}

Agrawal, Shipra ^{[3
]}

Reddy, B. A. Ashok ^{[2
]}

Roy, Siddhartha ^{[4
]}

Rangappa, K. S. ^{[1
]}

Kundu, Tapas K. ^{[2
]}

机构：

[1] Univ Mysore, Dept Studies Chem, Mysore 06, Karnataka, India

[2] Jawaharlal Nehru Ctr Adv Sci Res, Genet Unit, Bangalore 64, Karnataka, India

[3] ITPB, Inst Bioinformat & Appl Biotechnol, Bangalore, Karnataka, India

[4] Indian Inst Sci, Mol Biophys Unit, Bangalore 560012, Karnataka, India

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 04期

关键词：

D O I：

10.1021/jm700954w

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Aurora kinases are essential for chromosomal segregation and cell division and thereby important for maintaining the proper genomic integrity. There are three classes of aurora kinases in humans: A, B, and C. Aurora kinase A is frequently overexpressed in various cancers. The link of the overexpression and tumorigenesis is yet to be understood. By employing virtual screening, we have found that anacardic acid, a pentadecane aliphatic chain containing hydroxylcarboxylic acid, from cashew nut shell liquid could be docked in Aurora kinases A and B. Remarkably, we found that anacardic acid could potently activate the Aurora kinase A mediated phosphorylation of histone H3, but at a similar concentration the activity of aurora kinase B remained unaffected in vitro. Mechanistically, anacardic acid induces the structural changes and also the autophosphorylation of the aurora kinase A to enhance the enzyme activity. This data thus indicate anacardic acid as the first small-molecule activator of Aurora kinase, which could be highly useful for probing the function of hyperactive (overexpressed) Aurora kinase A.

引用

页码：792 / 797

页数：6

共 22 条

[1] Essential roles of Drosophila inner centromere protein (INCENP) and aurora B in histone H3 phosphorylation, metaphase chromosome alignment, kinetochore disjunction, and chromosome segregation [J].

Adams, RR ;

Maiato, H ;

Earnshaw, WC ;

Carmena, M .

JOURNAL OF CELL BIOLOGY, 2001, 153 (04) :865-879

[2] Chromosomal passengers and the (aurora) ABCs of mitosis [J].

Adams, RR ;

Carmena, M ;

Earnshaw, WC .

TRENDS IN CELL BIOLOGY, 2001, 11 (02) :49-54

[3] Small molecule modulators of histone acetyltransferase p300 [J].

Balasubramanyam, K ;

Swaminathan, V ;

Ranganathan, A ;

Kundu, TK .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (21) :19134-19140

[4] A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers [J].

Bischoff, JR ;

Anderson, L ;

Zhu, YF ;

Mossie, K ;

Ng, L ;

Souza, B ;

Schryver, B ;

Flanagan, P ;

Clairvoyant, F ;

Ginther, C ;

Chan, CSM ;

Novotny, M ;

Slamon, DJ ;

Plowman, GD .

EMBO JOURNAL, 1998, 17 (11) :3052-3065

[5] The Aurora/Ipi1p kinase family: regulators of chromosome segregation and cytokinesis [J].

Bischoff, JR ;

Plowman, GD .

TRENDS IN CELL BIOLOGY, 1999, 9 (11) :454-459

[6] The cellular geography of aurora kinases [J].

Carmena, M ;

Earnshaw, WC .

NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2003, 4 (11) :842-854

[7]

CHIPMAN DM, 1967, J BIOL CHEM, V242, P4388

[8] A novel mechanism for activation of the protein kinase aurora A [J].

Eyers, PA ;

Erikson, E ;

Chen, LG ;

Maller, JL .

CURRENT BIOLOGY, 2003, 13 (08) :691-697

[9] Ran induces spindle assembly by reversing the inhibitory effect of importin α on TPX2 activity [J].

Gruss, OJ ;

Carazo-Salas, RE ;

Schatz, CA ;

Guarguaglini, G ;

Kast, J ;

Wilm, M ;

Le Bot, N ;

Vernos, I ;

Karsenti, E ;

Mattaj, IW .

CELL, 2001, 104 (01) :83-93

[10]

Han HY, 2002, CANCER RES, V62, P2890

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