Aurora kinase inhibitors are a putative drug class for treating

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...

. The

Aurora kinase Aurora kinases are serine/threonine kinases that are essential for cell proliferation. They are phosphotransferase enzymes that help the dividing cell dispense its genetic materials to its daughter cells. More specifically, Aurora kinases play ...

enzymes could be potential targets for novel small-molecule

enzyme inhibitor An enzyme inhibitor is a molecule that binds to an enzyme and blocks its activity. Enzymes are proteins that speed up chemical reactions necessary for life, in which substrate molecules are converted into products. An enzyme facilitates a s ...

s. Aurora kinases regulate

cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA ( DNA replication) and some of its organelles, and sub ...

transit from G2 through

cytokinesis Cytokinesis () is the part of the cell division process during which the cytoplasm of a single eukaryotic cell divides into two daughter cells. Cytoplasmic division begins during or after the late stages of nuclear division in mitosis and me ...

, and thus are targets in

therapy. There are three

mammalian Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...

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 Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...

with aurora A identified as a low

penetrance Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (the genotype) that also express an associated trait (the phenotype). In medical genetics, the penetrance of a disease-causing mutation is ...

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

susceptibility gene in mice and humans.

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 In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is maint ...

. Aurora kinases, so named because the scattered

mitotic In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is mainta ...

spindles generated by mutant forms resemble the

Aurora Borealis An aurora (plural: auroras or aurorae), also commonly known as the polar lights, is a natural light display in Earth's sky, predominantly seen in high-latitude regions (around the Arctic and Antarctic). Auroras display dynamic patterns of b ...

, 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 A nucleosome is the basic structural unit of DNA packaging in eukaryotes. The structure of a nucleosome consists of a segment of DNA wound around eight histone proteins and resembles thread wrapped around a spool. The nucleosome is the fundamen ...

by phosphorylating

histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn ar ...

H3. Furthermore, Aurora kinases are known to be

oncogenic Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...

and overexpressed in various forms of cancerous growth, including

leukemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ...

colon cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel ...

prostate cancer Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that su ...

and

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or ...

tumors. So far three Aurora-kinase inhibitors have been described:

ZM447439 ZM447439 is an aurora inhibitor 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 ...

hesperadin Hesperadin is an aurora kinase inhibitor. The small molecule inhibits chromosome alignment and segregation by limiting the function of mitotic kinases Aurora B and Aurora A. Hesperadin causes cells to enter anaphase much faster, sometimes befor ...

and

VX-680 Tozasertib (VX-680) is an aurora inhibitor 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 cy ...

. The last is in advanced stages (Phase II

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

) of a joint drug development by

Vertex Pharmaceuticals Vertex Pharmaceuticals is an American biopharmaceutical company based in Boston, Massachusetts. It was one of the first biotech firms to use an explicit strategy of rational drug design rather than combinatorial chemistry. It maintains headqu ...

'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. File:ZM-447439.svg,

File:Hesperadin.svg,

Hesperadin Hesperadin is an aurora kinase inhibitor. The small molecule inhibits chromosome alignment and segregation by limiting the function of mitotic kinases Aurora B and Aurora A. Hesperadin causes cells to enter anaphase much faster, sometimes befor ...

File:VX680.svg,

Aurora structure

The structure and active site of Aurora-2-adenosine complex has been determined.Graham M. T. et al., Crystal Structure of Aurora-2, an Oncogenic Serine/Threonine Kinase J. Biol. Chem., (2002) 277: pp.42419-22 The hinge (yellow), glycine-rich loop (blue), and

activation loop In molecular biology, an intrinsically disordered protein (IDP) is a protein that lacks a fixed or ordered three-dimensional structure, typically in the absence of its macromolecular interaction partners, such as other proteins or RNA. IDPs ran ...

(red) are key features of the

protein kinase A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a fu ...

fold involved in binding

adenosine Adenosine (symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9-glycosidic bond. Adenosine is one of the four nucleoside buildin ...

. 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 In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a ...

. There are no hydrogen bonds between the 2'-OH or 3'-OH groups of the

ribose Ribose is a simple sugar and carbohydrate with molecular formula C5H10O5 and the linear-form composition H−(C=O)−(CHOH)4−H. The naturally-occurring form, , is a component of the ribonucleotides from which RNA is built, and so this compou ...

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.

References

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 Map The Proteolysis MAP (PMAP) 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 PMAP was originally create ...

-animation {{DEFAULTSORT:Aurora Inhibitors Cell cycle Mitosis Protein kinase inhibitors

Drug development

Aurora structure

See also

References

External links