Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.10 (IKK)
 4,900 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in aurora of Drosophila and related Saccharomyces cerevisiae IPL1 protein kinases are known to cause abnormal chromosome segregation. We earlier isolated a cDNA encoding a novel human protein kinase Aik which shares high amino acid identity with the Aurora/Ipl1 protein kinase family. In the present study, a second human cDNA highly homologous to aurora/IPL1 (Aik2) was identified and the nucleotide sequence was determined (gene symbol STK12). The C-terminal kinase domain of the STK12 encoded protein shares high amino acid sequence identity with those of mouse STK-1 (90%), rat AIM-1 (90%), human Aik (69%), mouse IAK1/Ayk1 (69%), Xenopus pEg2 (68%), Drosophila Aurora (62%), and yeast Ipl1 (45%), whereas the N-terminal domain of the STK12 protein shares little homology with those of Aurora/Ipl1 family members except for AIM-1 and STK-1. Northern blotting analyses revealed that STK12 expression was high in thymus, while low level expression was detected in small intestine, testis, colon, spleen, and brain. The STK12 protein content in HeLa cells is low in S phase, but it accumulates during M phase. STK12 was mapped to human chromosome 17p13.1 by fluorescence in situ hybridization. The chromosome location of STK12 was further defined using a radiation hybrid panel (Stanford G3), that showed a linkage with marker WI-7901 (LOD Score 7.83) located between D17S938 and D17S786.
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PMID:Identification and characterization of STK12/Aik2: a human gene related to aurora of Drosophila and yeast IPL1. 985 6

The aurora kinases are a novel oncogenic family of mitotic serine/threonine kinases (S/T kinases) that are overexpressed in a number of solid tumors, including pancreas and colorectal cancer. A PSI-BLAST search [National Center for Biotechnology Information (NCBI)] with the sequence of the S/T kinase domain of human aurora1 kinase [also known as AUR1, ARK2, AIk2, AIM-1, and STK12] and human aurora2 kinase (also known as AUR2, ARK1, AIK, BTAK, and STK15) showed a high sequence similarity to the three-dimensional structures of bovine cAMP-dependent kinase [Brookhaven Protein Data Bank code 1CDK], murine cAMP-dependent kinase (1APM), and Caenorhabditis elegans twitchin kinase (1KOA). When the aurora1 or aurora2 sequence was input into the tertiary structure prediction programs THREADER and 3D-PSSM (three-dimensional position-sensitive scoring matrix), the top structural matches were 1CDK, 1APM, and 1KOA, confirming that these domains are structurally conserved. The structural models of aurora1 and aurora2 were built using 1CDK as the template structure. Molecular dynamics and docking simulations, targeting the ATP binding site of aurora2 with adenylyl imidodiphosphate (AMP-PNP), staurosporine, and six small molecular S/T kinase inhibitors, identified active-site residues that interact with these inhibitors differentially. The docked structures of the aurora2-AMP-PNP and aurora2-staurosporine complexes indicated that the adenine ring of AMP-PNP and the indolocarbazole moiety of staurosporine have similar positions and orientations and provided the basis for the docking of the other S/T kinase inhibitors. Inhibitors with isoquinoline and quinazoline moieties were recognized by aurora2 in which H-89 and 6,7-dimethoxyquinazoline compounds exhibited high binding energies compared with that of staurosporine. The calculated binding energies for the docked small-molecule inhibitors were qualitatively consistent with the IC(50) values generated using an in vitro kinase assay. The aurora2 structural model provides a rational basis for site-directed mutagenesis of the active site; design of novel H-89, staurosporine, and quinazoline analogues; and the screening of the available chemical database for the identification of other novel, small-molecular entities.
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PMID:Targeting aurora2 kinase in oncogenesis: a structural bioinformatics approach to target validation and rational drug design. 1265 23

Aurora kinases A (also known as Aurora, Aurora-2, AIK, AIR-1, AIRK1, AYK1, BTAK, Eg2, MmIAK1 and STK15), Aurora B (also known as Aurora-1, AIM-1, AIK2, AIR-2, AIRK-2, ARK2, IAL-1 and STK12) and Aurora C (also known as AIK3) participate in several biological processes, including cytokinesis and dysregulated chromosome segregation. These important regulators of mitosis are over-expressed in diverse solid tumors. One member of this family of serine-threonine kinases, human Aurora A, has been proposed as a drugable target in pancreatic cancer. The recent determination of the three-dimensional structure of Aurora A has shown that Aurora kinases exhibit unique conformations around the activation loop region. This property has boosted the search and development of inhibitors of Aurora kinases, which might also function as novel antioncogenic agents.
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PMID:Aurora kinases. 1589 67

Large numbers of inhibitors for polo-like kinases and aurora kinases are currently being evaluated as anticancer drugs. Interest in these drugs is fuelled by the idea that these kinases have unique functions in mitosis. Within the polo-like kinase family, the emphasis for targeted therapies has been on polo-like kinase 1 (PLK1), and in the aurora kinase family drugs have been developed to specifically target aurora kinase A (AURKA; also known as STK6) and/or aurora kinase B (AURKB; also known as STK12). Information on the selectivity of these compounds in vivo is limited, but it is likely that off-target effects within the same kinase families will affect efficacy and toxicity profiles. In addition, it is becoming clear that interplay between polo-like kinases and aurora kinases is much more extensive than initially anticipated, and that both kinase families are important factors in the response to classical chemotherapeutics that damage the genome or the mitotic spindle. In this Review we discuss the implications of these novel insights on the clinical applicability of polo-like kinase and aurora kinase inhibitors.
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PMID:Shared and separate functions of polo-like kinases and aurora kinases in cancer. 2110 34