Aurora inhibitors
Encyclopedia
Aurora kinase
s regulate cell cycle
transit from G2 through cytokinesis
and, thus, are targets in cancer
therapy. 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 with aurora A identified as a low penetrance tumor
susceptibility gene
in mice and humans. Aurora kinases could be potential targets for novel small-molecule enzyme inhibitor
s.
growth that shows great promise for structure-based drug development is targeting enzymes central to cellular mitosis
. 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. The Aurora enzymes are particularly significant because they are involved in a direct path to the nucleosome
by phosphorylating histone
H3. Furthermore, Aurora kinases are known to be oncogenic and overexpressed in various forms of cancerous growth, including leukemia
, colon
cancer, prostate cancer
and breast cancer
tumors.
So far three Aurora-kinase inhibitors have been described: ZM447439
, Hesperadin
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.
, although the Phase II clinical trial was suspended in November, 2007 due to QT prolongation observed in one patient in Phase I trial.
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.
Aurora Kinase
Aurora kinases are serine/threonine kinases that are essential for cell proliferation. The enzyme helps the dividing cell dispense its genetic materials to its daughter cells. More specifically, Aurora kinases play a crucial role in cellular division by controlling chromatid segregation...
s regulate cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
transit from G2 through cytokinesis
Cytokinesis
Cytokinesis is the process in which the cytoplasm of a single eukaryotic cell is divided to form two daughter cells. It usually initiates during the late stages of mitosis, and sometimes meiosis, splitting a binucleate cell in two, to ensure that chromosome number is maintained from one generation...
and, thus, are targets in cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
therapy. There are three mammalian aurora kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
, encoding aurora A, B and C. Intense investigation has focused on aurora A and B as they appear to play a role in oncogenesis with aurora A identified as a low penetrance tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
susceptibility gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
in mice and humans. Aurora kinases could be potential targets for novel small-molecule enzyme inhibitor
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
s.
Drug development
A new approach to inhibiting cancerCancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
growth that shows great promise for structure-based drug development is targeting enzymes central to cellular mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
. 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. The Aurora enzymes are particularly significant because they are involved in a direct path to the nucleosome
Nucleosome
Nucleosomes are the basic unit of DNA packaging in eukaryotes, consisting of a segment of DNA wound around a histone protein core. This structure is often compared to thread wrapped around a spool....
by phosphorylating histone
Histone
In biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation...
H3. Furthermore, Aurora kinases are known to be oncogenic and overexpressed in various forms of cancerous growth, including leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
, colon
Colon (anatomy)
The colon is the last part of the digestive system in most vertebrates; it extracts water and salt from solid wastes before they are eliminated from the body, and is the site in which flora-aided fermentation of unabsorbed material occurs. Unlike the small intestine, the colon does not play a...
cancer, prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
and breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
tumors.
So far three Aurora-kinase inhibitors have been described: ZM447439
ZM447439
ZM447439 is an aurora inhibitor....
, Hesperadin
Hesperadin
Hesperadin is an aurora inhibitor....
and VX-680
VX-680
VX-680 is an aurora inhibitor....
. The last is in advanced stages (Phase II clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
) of a joint drug development by Vertex Pharmaceuticals
Vertex Pharmaceuticals
Vertex Pharmaceuticals is a biotechnology company with activities spanning the length of the pharmaceutical product pipeline, from target identification through to clinical trials and marketing. Most of its activity has been in collaboration with much larger pharmaceutical firms, though some of its...
's VX-680 (Sausville, 234, last posted on 12/18/06) and Merck & Co.
Merck & Co.
Merck & Co., Inc. , also known as Merck Sharp & Dohme or MSD outside the United States and Canada, is one of the largest pharmaceutical companies in the world. The Merck headquarters is located in Whitehouse Station, New Jersey, an unincorporated area in Readington Township...
, 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. The hinge (yellow), glycine-rich loop (blue), and activation loop (red) are key features of the protein kinaseProtein kinase
A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins...
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
Ribose
Ribose is an organic compound with the formula C5H10O5; specifically, a monosaccharide with linear form H––4–H, which has all the hydroxyl groups on the same side in the Fischer projection....
moiety and Aurora-2. Residues Lys-162 and Asp-274 are essential for Aurora-2 kinase activity but do not hydrogen bond
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...
to each other as seen in crystal structures of several other protein kinases.
External links
- Aurora-A (Serine/threonine-protein kinase 6, AIK, ARK1, AURA, BTAK, STK15, STK6)
- Aurora-B (Serine/threonine-protein kinase 12, AIK2, AIM1, ARK2, STK12)
- Aurora-C (Serine/threonine-protein kinase 13, AIE2, AIK3, STK13)
- Mitotic spindle & Aurora - PMAP The Proteolysis MapThe Proteolysis MapThe Proteolysis MAP is an integrated web resource focused on proteases.-Rationale:PMAP is to aid the protease researchers in reasoning about proteolytic networks and metabolic pathways.-History and funding:...
-animation