Specific Small-Molecule Activator of Aurora Kinase A Induces Autophosphorylation in a Cell-Free System

• Published in: Journal of medicinal chemistry Vol. 51; no. 4; pp. 792 - 797
• Main Authors: Kishore, A. Hari, Vedamurthy, B. M, Mantelingu, K, Agrawal, Shipra, Reddy, B. A. Ashok, Roy, Siddhartha, Rangappa, K. S, Kundu, Tapas K
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 28.02.2008
• Subjects: Anacardic Acids - chemistry; Anacardic Acids - isolation & purification; Anacardium; Analytical, structural and metabolic biochemistry; Aurora Kinase A; Aurora Kinase B; Aurora Kinases; Biological and medical sciences; Cell Line; Cloning, Molecular; Crystallography, X-Ray; Enzyme Activators - chemistry; Enzyme Activators - isolation & purification; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Histones - chemistry; Humans; Kinetics; Medical sciences; Miscellaneous; Models, Molecular; Molecular Structure; Pharmacology. Drug treatments; Phosphorylation; Protein-Serine-Threonine Kinases - chemistry; Protein-Serine-Threonine Kinases - genetics; Spectrometry, Fluorescence; Transferases; Autophosphorylation; Enzyme; Anacardium occidentale; Transferases; Non-specific serine/threonine protein kinase; Association constant; Virtual screening; Fluorescence; Stability constant; Biological activity; Signal transduction; Activator; Dicotyledones; Angiospermae; Isolation; Spermatophyta; Fruit tree; Small molecule; Mechanism of action; Cell free system; Cashew nut; Anacardiaceae
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm700954w

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.