GLORIA

GEOMAR Library Ocean Research Information Access

X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Online Resource
    Online Resource
    A Small-Molecule Inhibitor of PIM Kinases as a Potential Treatment for Urothelial Carcinomas
    Elsevier BV ; 2014
    In:  Neoplasia Vol. 16, No. 5 ( 2014-05), p. 403-412
    Details
    In: Neoplasia, Elsevier BV, Vol. 16, No. 5 ( 2014-05), p. 403-412
    Type of Medium: Online Resource
    ISSN: 1476-5586
    URL: Article
    DOI: 10.1016/j.neo.2014.05.004
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2014
    detail.hit.zdb_id: 2008231-9
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 2
    Online Resource
    Online Resource
    Abstract 2174: Small molecule iInhibitors of PIM kinases as potential treatments for urothelial carcinomas.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2174-2174
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2174-2174
    Abstract: The proto-oncogene PIM kinases (PIM-1, PIM-2, PIM-3) are serine/threonine kinases that have been shown to be involved in a number of signaling pathways important to cancer cells. PIM kinases act as downstream effectors as inhibitors of apoptosis and as positive regulators of G1-S phase progression through the cell cycle. PIM kinases are upregulated in multiple cancer indications, including lymphoma, leukemia, multiple myeloma, prostate, gastric, and head & neck cancers. Overexpression of one or more PIM family members in patient tumors frequently correlates with poor prognosis. The aim of this investigation was to evaluate PIM expression in low- and high-grade urothelial carcinoma, and to assess for expression that may contribute to disease progression and serve as a potential site for targeted therapy. Seventy-two cases of urothelial carcinoma were included in this retrospective study of surgical biopsy and resection specimens from the University of Utah Department of Pathology (retrieved from 2008-2011). Tissue was stained with commercially available antibodies against PIM-1, PIM-2, and PIM-3. Cases were divided into three groups (invasive high grade urothelial carcinoma (n=49), non-invasive urothelial carcinoma/carcinoma in situ (n=16), and non-invasive low grade urothelial carcinoma (n=7)). Individual cases were then given a score (0-4) based upon a percentage of cells staining positive for each antibody ( & lt;5%=0; 5-25%=1; 26-50%=2; 51-75%=3; & gt;75%=4). A score of 2 or greater was considered expressed. PIM-1, PIM-2 and PIM-3 expression was noted in 29% (2/7), 43% (3/7) and 86% (6/7) cases of non-invasive low-grade urothelial carcinoma; 44% (7/16), 50% (8/16), 44% (7/16) cases of non-invasive high-grade urothelial carcinoma; 10% (5/49), 27% (13/49), and 18% (9/49) cases of invasive high-grade urothelial carcinoma, respectively. These results suggest that expression of PIM-1, PIM-2 and PIM-3 is present in a significant percentage of urothelial carcinomas and may serve as a source for targeted PIM-kinase inhibition. We have developed PIM inhibitors exhibiting 4-10 fold improved potency against the PIM kinase family compared to our original PIM inhibitor SGI-1776. Our PIM inhibitors display sub-μM activity in pharmacodynamic marker modulation, proliferation and 2D colony formation assays using the UM-UC-3 bladder cancer cell line. These PIM kinase inhibitors also are potent inducers of apoptosis in T24, RT4, and UM-UC-3 bladder cancer cell lines. These compounds have favorable hERG and CYP inhibition profiles compared with SGI-1776, and demonstrate excellent oral bioavailability. In vivo xenograft studies using bladder cancer cell line models show that PIM kinase inhibition can reduce the tumor growth of these tumor models suggesting that PIM kinase inhibitors may be active in human urothelial carcinomas. Citation Format: Kent J. Carpenter, Rachel Brog, Christopher Moreno, Daniel J. Albertson, Jared J. Bearss, Ting Liu, Steven Warner, David J. Bearss. Small molecule iInhibitors of PIM kinases as potential treatments for urothelial carcinomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2174. doi:10.1158/1538-7445.AM2013-2174
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-2174
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 3
    Online Resource
    Online Resource
    Discovery of Novel Putative Inhibitors of UDP-GlcNAc 2-Epimerase as Potent Antibacterial Agents
    American Chemical Society (ACS) ; 2013
    In:  ACS Medicinal Chemistry Letters Vol. 4, No. 12 ( 2013-12-12), p. 1142-1147
    Details
    In: ACS Medicinal Chemistry Letters, American Chemical Society (ACS), Vol. 4, No. 12 ( 2013-12-12), p. 1142-1147
    Type of Medium: Online Resource
    ISSN: 1948-5875 , 1948-5875
    URL: Article
    DOI: 10.1021/ml4001936
    Language: English
    Publisher: American Chemical Society (ACS)
    Publication Date: 2013
    detail.hit.zdb_id: 2532386-6
    SSG: 15,3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 4
    Online Resource
    Online Resource
    Abstract 5543: Inhibition of the tyrosine kinase receptor Axl blocks cell invasion and promotes apoptosis in pancreatic cancer cells.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 5543-5543
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 5543-5543
    Abstract: Pancreatic cancer is virtually a uniformly lethal disease and a better understanding of the molecular basis of this malignancy is needed to discover new ways to prevent or treat this deadly disease. A central feature of malignant cells is their ability to disseminate from the primary tumor and establish local and distant metastases. In most cases, cancer patients with localized disease have significantly better prognosis than those with metastatic tumors and the majority of cancer mortality is associated with metastatic disease rather than the primary tumor. The receptor tyrosine kinase Axl is overexpressed in over 50% of pancreatic cancers and expression of Axl in these cancers is highly associated with a poor prognostic outcome for patients. Axl is a TAM family receptor tyrosine kinase involved in multiple aspects of tumorigenesis. Increased expression of Axl is associated with increased oncogenic transformation, cell survival, proliferation, migration, angiogenesis, and cellular adhesion. The known ligand for Axl is the Growth Arrest Specific Gene-6 (Gas6) protein and it's binding to Axl leads to Axl autophosphorylation and activation of downstream signaling pathways including MAPK and PI3K/Akt pathways. We discovered and developed a small molecule Axl kinase inhibitor, HCI-2084, and explored it for the effectiveness of targeting the Axl kinase in cell-based models of pancreatic cancer. HCI-2084 is a 2-((2,5-substitutedpyrimidin-4-yl)amino)-N,N-dimethyl benzene sulfonamide that has low nanomolar (IC50 = 12 nM) activity against the Axl kinase in a biochemical assays. In further biochemical evaluation, HCI-2084 was shown to inhibit the entire TAM family of kinases (IC50 Axl = 12 nM; IC50 Mer = 60 nM; Tyro3 = 71% inhibition at 200 nM). HCI-2084 inhibits a small number of additional kinases when screened in a kinase panel of over 500 kinases and has demonstrated an ADMET profile suggesting it may be a potential clinical candidate. In cell proliferation assays, HCI-2084 significantly inhibited pancreatic cancer cell growth at concentrations as low as 30 nM. In pharmacodynamic assays, HCI-2084 dramatically inhibited Akt signaling (pAKT S473) downstream of GAS6 stimulation in pancreatic cancer cell lines. Consistent with the known function of Axl, HCI-2084 inhibited Gas6-induced migration and invasion of pancreatic cancer cells in vitro and potently induces apoptosis. Mechanistically, HCI-2084 decreases the expression of genes involved in Epithelial-Mesenchymal Transition (EMT) and induces cells to take on more epithelial phenotypes. HCI-2084 also significantly inhibited the growth of pancreatic cancer cell lines grown in xenograft tumor mouse model and taken together, these results suggest Axl is a potential therapeutic target in pancreatic cancer and that HCI-2084 is a potential agent treat this disease. Citation Format: Malia Anderson, Alex Ober, Alexis Mollard, Lee Call, Jared J. Bearss, Hariprasad Vankayalapati, Sunil Sharma, Steven Warner, David J. Bearss. Inhibition of the tyrosine kinase receptor Axl blocks cell invasion and promotes apoptosis in pancreatic cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5543. doi:10.1158/1538-7445.AM2013-5543
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-5543
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 5
    Online Resource
    Online Resource
    Abstract 2577: Targeting the Axl tyrosine kinase receptor in pancreatic cancer
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2577-2577
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2577-2577
    Abstract: With the worst five-year survival rate of any cancer, pancreatic adenocarcinomas now rank as the fourth leading cause of cancer death in adults in the United States. This necessitates increased efforts to identify new leads that will serve as therapeutic targets in our fight against this aggressive cancer. Axl is a TAM family receptor tyrosine kinase involved in multiple aspects of tumorigenesis. Increased expression of Axl is associated with increased oncogenic transformation, cell survival, proliferation, migration, angiogenesis, and cellular adhesion. The oncogenic potential of Axl was first discovered in chronic myelogenous leukemia (CML), but it has been demonstrated to play a role in the progression and metastasis of other cancer types. The known ligand for Axl is the Growth Arrest Specific Gene-6 (Gas6) protein and its binding to Axl leads to Axl autophosphorylation and activation of downstream signaling pathways including MAPK and PI3K/Akt pathways. Furthermore, target validation studies of in vivo cancer models show that inhibition of Axl expression by RNAi blocked tumor growth in those models. Taken together, this information makes Axl kinase an exciting target for small molecule drug discovery. Using HCI-2084, a small molecule Axl kinase inhibitor, we explored the effectiveness of targeting the Axl kinase in pancreatic cancer. HCI-2084 demonstrates low nanomolar (IC50 = 12 nM) activity against the Axl kinase in a biochemical assay with good selectivity for Axl when screened in a kinase panel. In 2D and 3D cell proliferation assays, HCI-2084 significantly inhibited pancreatic cancer cell growth at concentrations as low as 30 nM. In pharmacodynamic endpoint assays, HCI-2084 dramatically inhibited Akt signaling (pAKT S473) downstream of GAS6 stimulation in pancreatic cancer cell lines. Inhibition of Axl autophosphorylation by HCI-2084 was also observed in an Axl-transfected cell line system. Consistent with the known function of Axl, HCI-2084 inhibited Gas6-induced migration and invasion of pancreatic cancer cells in vitro. The proteolytic processing of the extracellular domain of the Axl receptor is a known event downstream of Axl activation and results in the release of soluble Axl (sAxl) into the cell culture media (in vitro) or into the blood stream (in vivo). We hypothesized that sAxl levels could function as a biomarker for target inhibition. Indeed, conditioned media from pancreatic cancer cell lines treated with HCI-2084 showed significant dose-dependent reductions in sAxl levels compared to the vehicle treated controls. Taken together, these results suggest Axl is a potential therapeutic target in pancreatic cancer and that HCI-2084 is an exciting agent to potentially treat this disease. HCI-2084 is currently undergoing evaluation in animal efficacy and pharmacodynamic endpoint studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2577. doi:10.1158/1538-7445.AM2011-2577
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-2577
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 6
    Online Resource
    Online Resource
    Novel Series of ALK2 Inhibitors That Alter Hepcidin Expression As Potential Therapeutics for Anemia of Chronic Disease
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 212-212
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 212-212
    Abstract: Anemia of chronic disease (ACD) is an inflammatory cytokine driven disease characterized by hypoferremia despite adequate iron stores. This is largely due to hepcidin, a master regulator of iron homeostasis, which blocks enterocytes from absorbing iron and preventing iron release from macrophages by binding to ferroportin. It is known that bone morphogenetic proteins (BMP) up-regulate hepcidin by activating the SMAD signaling pathway through the activin-like kinase receptor 2 (ALK2). Therefore, ALK2 has emerged as a potential therapeutic target to modulate hepcidin levels and treat ACD. We have developed a novel series of small molecule ALK2 inhibitors with promising activity in preclinical models of ACD. Using well-established cell-based and animal models of hepcidin signaling and anemia, we optimized and validated the activity of the most promising preclinical lead candidates. These compounds demonstrate significant activity in downregulating hepcidin expression in BMP-induced cell culture studies at concentrations of 100 nM or lower. Importantly, this hepcidin lowering activity was observed at concentrations that exhibited no cytotoxicity suggesting the compounds have a clean selectivity profile. The compounds also demonstrated remarkable activity in animal models of anemia, including an acute model induced by the administration of turpentine oil and a more chronic model induced by tumor formation and growth. Treatment with the lead candidates completely reversed the induction of hepcidin expression in these models and also decreased the symptoms of anemia as measured by serum iron and red blood cell levels. From these data, we have nominated a candidate to advance into IND-enabling studies that has favorable drug-like properties. We anticipate a clinical development strategy that focuses on anemia of cancer with subsequent expansion into anemia associated more broadly with other inflammatory and chronic diseases Disclosures Kim: Tolero Pharmaceuticals: Employment. Maughan:Tolero Pharmaceuticals: Employment. Soh:Tolero Pharmaceuticals: Employment. Bearss:Tolero Pharmaceuticals: Employment. Bahr:Tolero Pharmaceuticals: Employment. Bearss:Tolero Pharmaceuticals: Employment. Warner:Tolero Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.212.212
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 7
    Online Resource
    Online Resource
    Abstract 2788: Design, optimization, and biological evaluation of potent irreversible inhibitors of BTK kinase
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2788-2788
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2788-2788
    Abstract: Bruton's tyrosine kinase (BTK) is a cytoplasmic nonreceptor tyrosine kinase belonging to the Tec family of kinases. Critical for its function, BTK contains a pleckstrin homology (PH) domain and Src homology SH3 and SH2 domains. It signals downstream of the B-cell receptor (BCR) and is centrally involved in B-cell development. Activation of B-cells by various ligands is accompanied by the translocation of BTK to the cell membrane where it binds phosphatidylinositol-3,4,5-trisphosphate through its PH domain. Activation of BTK results in downstream signaling through the PI3K/AKT, PLCγ, NFκB, and other signaling pathways important for B-cell development and function. Recent reports have shown the aberrant expression and function of BTK in some cancers, including B-cell malignancies. We describe here the design, synthesis, molecular modeling, and biological evaluation of a series of small molecule, inhibitors of BTK kinase. Our initial lead compounds were identified via cross-docking experiments utilizing the crystal structure of BTK kinase and screening a previously in-house explored kinase inhibitor scaffold. We subsequently carried out structure-activity relationship studies and optimized the lead structures, which have IC50 activities in the range of 1 to 10μM against BTK. A critical step in the optimization of this chemical series against BTK was to explore the possibility of adding a Michael's acceptor group to react with Cys481 in the ATP-binding pocket of BTK. Optimization efforts yielded the currently best leads, HCI-1684 and HCI-1685, which inhibit BTK with IC50 values of 12 and 45 nM, respectively. Modeling data suggest these compounds irrepressibly bind in the ATP-binding pocket of BTK. HCI-1684, HCI-1685 and other lead compounds were further evaluated in cell-based assays and were demonstrated to inhibit BTK function downstream of BCR activation. This series of BTK inhibitors were shown to decrease phospho-PLCγ1/2 levels and other downstream phosphorylation events in malignant B-cell cell lines, such as Ramos B. Compound optimization and biological evaluation of this chemical series and evaluation in animal pharmacodynamic endpoint studies will be presented. Taken together, these results suggest BTK is a potential therapeutic target in cancer and that HCI-1684 is an exciting agent to potentially treat B-cell malignancies Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2788. doi:10.1158/1538-7445.AM2011-2788
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-2788
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 8
    Online Resource
    Online Resource
    Design, Synthesis, and Biological Evaluation of a Series of Novel AXL Kinase Inhibitors
    American Chemical Society (ACS) ; 2011
    In:  ACS Medicinal Chemistry Letters Vol. 2, No. 12 ( 2011-12-08), p. 907-912
    Details
    In: ACS Medicinal Chemistry Letters, American Chemical Society (ACS), Vol. 2, No. 12 ( 2011-12-08), p. 907-912
    Type of Medium: Online Resource
    ISSN: 1948-5875 , 1948-5875
    URL: Article
    DOI: 10.1021/ml200198x
    Language: English
    Publisher: American Chemical Society (ACS)
    Publication Date: 2011
    detail.hit.zdb_id: 2532386-6
    SSG: 15,3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 9
    Online Resource
    Online Resource
    Abstract 3609: Homology structure-based design, synthesis and biological evaluation of a series of novel Axl and Mer kinase inhibitors
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3609-3609
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3609-3609
    Abstract: Axl and Mer kinases belong to the TAM family that was first identified as a transforming gene in chronic myeloid leukemia. Its intracellular region has the typical receptor tyrosine kinase (RTK) structure and its extracellular domain is similar to cadherin-type adhesion molecules in that it is composed of fibronectin type II and immunoglobulin (Ig) motifs. Axl binds various growth factors, with vitamin K-dependent protein growth-arrest-specific gene 6 (GAS6) being the best studied. Axl is involved in mesenchymal and neuronal development as well as in cell survival, adhesion and blood vessel function. High levels of Axl are found in various tumors, including malignant glioma and metastatic colon, ovarian and breast cancers, and it plays a role in cancer invasion. Recent development of Axl inhibitors suggested that inhibition of Axl activity may be impact both tumor angiogenesis and tumor growth. We describe here the design, synthesis, molecular modeling, and biological evaluation of a series of small molecule, inhibitors of Axl and Mer kinases. Our initial lead compound was identified via cross-docking experiments utilizing the homology model of Axl kinase and screening of a diverse in-house chemical library. We subsequently carried out structure-activity relationship studies and optimized the lead structure which has 2 to 6.1 μM inhibition activity to 2-fold improvement in the Axl and Mer kinase activities to 730 nM. As a starting point for further optimization, it was considered that the modest of these series could be improved by introducing a spacer at the aryl piperazine moiety and focused on maximizing the in vitro potency, addressing the SAR and molecular properties. We further explored Leu620, hydrophobic, Gly543, Phe547 and DFG motif sites through scaffold hoping lead to the identification of an electron-withdrawing functional groups lead to the compound HCI-2084 and HCI-2091 which exhibited potent Axl kinase inhibition activity of 7 and 12 nM in Axl kinase assay and 30-50 nM is panel of cancer cell lines. These novel series of compounds were synthesized in two-step procedure via a standard cross-coupling reaction or with various substituted aryl amine derivatives under amination conditions. In a subsequent step we employed Buchwald-Hartwig amination reaction to prepare target molecules. Due to the ready synthesis accessibility, we extensively investigated the SAR improving the RO5, solubility and permeability parameters. The details of these results will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3609. doi:10.1158/1538-7445.AM2011-3609
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-3609
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 10
    Online Resource
    Online Resource
    S110, a 5-Aza-2′-Deoxycytidine–Containing Dinucleotide, Is an Effective DNA Methylation Inhibitor In vivo and Can Reduce Tumor Growth
    American Association for Cancer Research (AACR) ; 2010
    In:  Molecular Cancer Therapeutics Vol. 9, No. 5 ( 2010-05-01), p. 1443-1450
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 9, No. 5 ( 2010-05-01), p. 1443-1450
    Abstract: Methylation of CpG islands in promoter regions is often associated with gene silencing and aberrant DNA methylation occurs in most cancers, leading to the silencing of some tumor suppressor genes. Reversal of this abnormal hypermethylation by DNA methylation inhibitors is effective in reactivating methylation-silenced tumor suppressor genes both in vitro and in vivo. Several DNA methylation inhibitors have been well studied; the most potent among them is 5-aza-2′-deoxycytidine (5-Aza-CdR), which can induce myelosuppression in patients. S110 is a dinucleotide consisting of 5-Aza-CdR followed by a deoxyguanosine, which we previously showed to be effective in vitro as a DNA methylation inhibitor while being less prone to deamination by cytidine deaminase, making it a promising alternative to 5-Aza-CdR. Here, we show that S110 is better tolerated than 5-Aza-CdR in mice and is as effective in vivo in inducing p16 expression, reducing DNA methylation at the p16 promoter region, and retarding tumor growth in human xenograft. We also show that S110 is effective by both i.p. and s.c. deliveries. S110 therefore is a promising new agent that acts similarly to 5-Aza-CdR and has better stability and less toxicity. Mol Cancer Ther; 9(5); 1443–50. ©2010 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-09-1048
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
    detail.hit.zdb_id: 2062135-8
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...