Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.26 (GSK)
 6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cell cycle is an evolutionarily conserved process necessary for mammalian cell growth and development. Because cell-cycle aberrations are a hallmark of cancer, this process has been the target of anti-cancer therapeutics for decades. However, despite numerous clinical trials, cell-cycle-targeting agents have generally failed in the clinic. This review briefly examines past cell-cycle-targeted therapeutics and outlines how experience with these agents has provided valuable insight to refine and improve anti-mitotic strategies. An overview of emerging anti-mitotic approaches with promising pre-clinical results is provided, and the concept of exploiting the genomic instability of tumor cells through therapeutic inhibition of mitotic checkpoints is discussed. We believe this strategy has a high likelihood of success given its potential to enhance therapeutic index by targeting tumor-specific vulnerabilities. This reasoning stimulated our development of novel inhibitors targeting the critical regulators of genomic stability and the mitotic checkpoint: AURKA, PLK4, and Mps1/TTK.
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PMID:Targeting Mitosis in Cancer: Emerging Strategies. 2659 Jul 12

Deregulation of the cell cycle is a hallmark of cancer that enables limitless cell division. To support this malignant phenotype, cells acquire molecular alterations that abrogate or bypass control mechanisms in signaling pathways and cellular checkpoints that normally function to prevent genomic instability and uncontrolled cell proliferation. Consequently, therapeutic targeting of the cell cycle has long been viewed as a promising anti-cancer strategy. Until recently, attempts to target the cell cycle for cancer therapy using selective inhibitors have proven unsuccessful due to intolerable toxicities and a lack of target specificity. However, improvements in our understanding of malignant cell-specific vulnerabilities has revealed a therapeutic window for preferential targeting of the cell cycle in cancer cells, and has led to the development of agents now in the clinic. In this review, we discuss the latest generation of cell cycle targeting anti-cancer agents for breast cancer, including approved CDK4/6 inhibitors, and investigational TTK and PLK4 inhibitors that are currently in clinical trials. In recognition of the emerging population of ER+ breast cancers with acquired resistance to CDK4/6 inhibitors we suggest new therapeutic avenues to treat these patients. We also offer our perspective on the direction of future research to address the problem of drug resistance, and discuss the mechanistic insights required for the successful implementation of these strategies.
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PMID:Targeting the cell cycle in breast cancer: towards the next phase. 3007 54

Multiple myeloma (MM) account for approximately 10% of hematological malignancies and is the second most common hematological disorder. Kinases inhibitors are widely used and their efficiency for the treatment of cancers has been demonstrated. Here, in order to identify kinases of potential therapeutic interest for the treatment of MM, we investigated the prognostic impact of the kinome expression profile in large cohorts of patients. We identified 36 kinome-related genes significantly linked with a prognostic value to MM, and built a kinome index based on their expression. The Kinome Index (KI) is linked to prognosis, proliferation, differentiation, and relapse in MM. We then tested inhibitors targeting seven of the identified protein kinas-es (PBK, SRPK1, CDC7-DBF4, MELK, CHK1, PLK4, MPS1/TTK) in human myeloma cell lines. All tested inhibitors significantly reduced the viability of myeloma cell lines, and we confirmed the potential clinical interest of three of them on primary myeloma cells from patients. In addition, we demonstrated their ability to potentialize the toxicity of conventional treatments, including Melphalan and Lenalidomide. This highlights their potential beneficial effect in myeloma therapy. Three kinases inhibitors (CHK1i, MELKi and PBKi) overcome resistance to Lenalidomide, while CHK1, PBK and DBF4 inhibitors re-sensitize Melphalan resistant cell line to this conventional therapeutic agent. Altogether, we demonstrate that kinase inhibitors could be of therapeutic interest especially in high-risk myeloma patients defined by the KI. CHEK1, MELK, PLK4, SRPK1, CDC7-DBF4, MPS1/TTK and PBK inhibitors could represent new treatment options either alone or in combination with Melphalan or IMiD for refractory/relapsing myeloma patients.
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PMID:Kinome expression profiling to target new therapeutic avenues in multiple myeloma. 3128 5

Cancer stem cells (CSCs) with self-renewal play an important role in tumor initiation and progression and are associated with drug resistance in cancer therapy. Here, we investigated the characteristics of stem cell-related genes in colorectal cancer (CRC) based on datasets from The Cancer Genome Atlas (TCGA) and Oncomine. We found that the stemness indices were significantly overexpressed in CRC tissues and were associated with patient survival. Weighted gene co-expression network analysis (WGCNA) was performed to determine the modules of stemness and featured genes. Significant modules and 8 genes (BUB1, BUB1B, CHEK1, DNA2, KIF23, MCM10, PLK4, and TTK) were selected according to the inclusion criteria. Expression analyses of transcription and protein levels confirmed internal correlation and their relevance with the tumor. Functional analysis of these genes demonstrated their enrichment in pathways, including checkpoint, chromosomal region and protein serine/threonine kinase activity. These results suggested that the characteristics of the featured genes fit well with CRC pathology and could provide new strategies for individual prevention and treatment.
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PMID:Characteristic Analysis of Featured Genes Associated With Stemness Indices in Colorectal Cancer. 3313 13

Osteosarcoma (OS) is a cancerous tumor in a bone. We aimed to identify the critical genes involved in OS progression, and then try to elucidate the molecular mechanisms of this disease. The microarray data of GSE32395 was used for the present study. We analyzed differentially expressed genes (DEGs) in OS cells compared with control group by Student's t-test. The significant enriched gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) pathways were analyzed for upregulated genes and downregulated genes, respectively. In addition, a protein-protein interaction (PPI) network was constructed. GO and KEGG enrichment analyses were conducted for genes in the PPI network. In total, 183 DEGs, including 100 upregulated DEGs and 83 downregulated DEGs were screened. The upregulated DEGs were significantly enriched in 2 KEGG pathways, such as "Glycosaminoglycan biosynthesis-chondroitin sulfate" and the downregulated DEGs were significantly enriched in 12 pathways, including "cell adhesion molecules," "pentose phosphate pathway" and "allograft rejection." GO enrichment analysis indicated that the upregulated DEGs were significantly involved in biological process, such as "multicellular organismal metabolic process" and "limb morphogenesis," while the downregulated DEGs were significantly enriched in biological process, such as "Positive regulation of pathway-restricted SMAD protein phosphorylation." The PPI network included 84 interactions and 51 nodes. The "glycosaminoglycan biosynthesis-chondroitin sulfate pathway," "microtubule motor activityfunction," and "regulation of mitosis process" were significantly enriched by genes in PPI network. In particular, CENPE, PRC1, TTK, and PLK4 had higher degrees in the PPI network. The interactions between TTK and PLK4 as well as CENPE and PRC1 may involve in the OS development. These 4 genes might be possible biomarkers for the treatment and diagnosis of OS.
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PMID:CENPE, PRC1, TTK, and PLK4 May Play Crucial Roles in the Osteosarcoma Progression. 3317 97