ALBERT

All Library Books, journals and Electronic Records Telegrafenberg

X
feed icon rss

Your email was sent successfully. Check your inbox.

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

Proceed reservation?

Export
  • 1
    facet.materialart.
    Unknown
    Novel mutant-selective EGFR kinase inhibitors against EGFR T790M (2009)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2009-12-25
    Description: The clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors in EGFR-mutant non-small-cell lung cancer (NSCLC) is limited by the development of drug-resistance mutations, including the gatekeeper T790M mutation. Strategies targeting EGFR T790M with irreversible inhibitors have had limited success and are associated with toxicity due to concurrent inhibition of wild-type EGFR. All current EGFR inhibitors possess a structurally related quinazoline-based core scaffold and were identified as ATP-competitive inhibitors of wild-type EGFR. Here we identify a covalent pyrimidine EGFR inhibitor by screening an irreversible kinase inhibitor library specifically against EGFR T790M. These agents are 30- to 100-fold more potent against EGFR T790M, and up to 100-fold less potent against wild-type EGFR, than quinazoline-based EGFR inhibitors in vitro. They are also effective in murine models of lung cancer driven by EGFR T790M. Co-crystallization studies reveal a structural basis for the increased potency and mutant selectivity of these agents. These mutant-selective irreversible EGFR kinase inhibitors may be clinically more effective and better tolerated than quinazoline-based inhibitors. Our findings demonstrate that functional pharmacological screens against clinically important mutant kinases represent a powerful strategy to identify new classes of mutant-selective kinase inhibitors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879581/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879581/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Wenjun -- Ercan, Dalia -- Chen, Liang -- Yun, Cai-Hong -- Li, Danan -- Capelletti, Marzia -- Cortot, Alexis B -- Chirieac, Lucian -- Iacob, Roxana E -- Padera, Robert -- Engen, John R -- Wong, Kwok-Kin -- Eck, Michael J -- Gray, Nathanael S -- Janne, Pasi A -- P50CA090578/CA/NCI NIH HHS/ -- R01 CA122794/CA/NCI NIH HHS/ -- R01 CA130876/CA/NCI NIH HHS/ -- R01 CA130876-02/CA/NCI NIH HHS/ -- R01 CA135257/CA/NCI NIH HHS/ -- R01AG2400401/AG/NIA NIH HHS/ -- R01CA080942/CA/NCI NIH HHS/ -- R01CA11446/CA/NCI NIH HHS/ -- R01CA116020/CA/NCI NIH HHS/ -- R01CA130876-02/CA/NCI NIH HHS/ -- R01CA135257/CA/NCI NIH HHS/ -- R01GM070590/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Dec 24;462(7276):1070-4. doi: 10.1038/nature08622.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20033049" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antineoplastic Agents/chemistry/*pharmacology/toxicity ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drug Evaluation, Preclinical ; Drug Resistance, Neoplasm/genetics ; Lung/drug effects ; Mice ; Models, Chemical ; Models, Molecular ; Mutation/*genetics ; NIH 3T3 Cells ; Phosphorylation/drug effects ; Protein Kinase Inhibitors/chemistry/*pharmacology/toxicity ; Receptor, Epidermal Growth Factor/*antagonists & inhibitors/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
    Location Call Number Expected Availability
    BibTip Others were also interested in ...
    PAPER CURRENT
  • 2
    facet.materialart.
    Unknown
    EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumours to TopoII inhibitors (2015)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2015-01-30
    Description: Non-small-cell lung cancer is the leading cause of cancer-related death worldwide. Chemotherapies such as the topoisomerase II (TopoII) inhibitor etoposide effectively reduce disease in a minority of patients with this cancer; therefore, alternative drug targets, including epigenetic enzymes, are under consideration for therapeutic intervention. A promising potential epigenetic target is the methyltransferase EZH2, which in the context of the polycomb repressive complex 2 (PRC2) is well known to tri-methylate histone H3 at lysine 27 (H3K27me3) and elicit gene silencing. Here we demonstrate that EZH2 inhibition has differential effects on the TopoII inhibitor response of non-small-cell lung cancers in vitro and in vivo. EGFR and BRG1 mutations are genetic biomarkers that predict enhanced sensitivity to TopoII inhibitor in response to EZH2 inhibition. BRG1 loss-of-function mutant tumours respond to EZH2 inhibition with increased S phase, anaphase bridging, apoptosis and TopoII inhibitor sensitivity. Conversely, EGFR and BRG1 wild-type tumours upregulate BRG1 in response to EZH2 inhibition and ultimately become more resistant to TopoII inhibitor. EGFR gain-of-function mutant tumours are also sensitive to dual EZH2 inhibition and TopoII inhibitor, because of genetic antagonism between EGFR and BRG1. These findings suggest an opportunity for precision medicine in the genetically complex disease of non-small-cell lung cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4393352/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4393352/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fillmore, Christine M -- Xu, Chunxiao -- Desai, Pooja T -- Berry, Joanne M -- Rowbotham, Samuel P -- Lin, Yi-Jang -- Zhang, Haikuo -- Marquez, Victor E -- Hammerman, Peter S -- Wong, Kwok-Kin -- Kim, Carla F -- CA120964/CA/NCI NIH HHS/ -- CA122794/CA/NCI NIH HHS/ -- CA140594/CA/NCI NIH HHS/ -- CA154303/CA/NCI NIH HHS/ -- CA163896/CA/NCI NIH HHS/ -- CA166480/CA/NCI NIH HHS/ -- K08 CA163677/CA/NCI NIH HHS/ -- R01 CA140594/CA/NCI NIH HHS/ -- R01 CA163896/CA/NCI NIH HHS/ -- R01 CA166480/CA/NCI NIH HHS/ -- R01 HL090136/HL/NHLBI NIH HHS/ -- U01 HL100402/HL/NHLBI NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2015 Apr 9;520(7546):239-42. doi: 10.1038/nature14122. Epub 2015 Jan 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts 02115, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA. ; 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. ; Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts 02115, USA. ; Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, USA. ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25629630" target="_blank"〉PubMed〈/a〉
    Keywords: Anaphase/drug effects ; Animals ; Antineoplastic Agents, Phytogenic/pharmacology/therapeutic use ; Apoptosis/drug effects ; Carcinoma, Non-Small-Cell Lung/drug therapy/enzymology/genetics/pathology ; Cell Cycle/drug effects ; Cell Line, Tumor ; DNA Helicases/*genetics ; Etoposide/pharmacology/therapeutic use ; Genes, erbB-1/*genetics ; Humans ; Lung Neoplasms/*drug therapy/enzymology/*genetics/pathology ; Mice ; Molecular Targeted Therapy ; Nuclear Proteins/*genetics ; Polycomb Repressive Complex 2/*antagonists & inhibitors ; Topoisomerase II Inhibitors/*pharmacology/*therapeutic use ; Transcription Factors/*genetics ; Xenograft Model Antitumor Assays
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
    Location Call Number Expected Availability
    BibTip Others were also interested in ...
    PAPER CURRENT
  • 3
    facet.materialart.
    Unknown
    The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-12-03
    Description: Thalidomide-like drugs such as lenalidomide are clinically important treatments for multiple myeloma and show promise for other B cell malignancies. The biochemical mechanisms underlying their antitumor activity are unknown. Thalidomide was recently shown to bind to, and inhibit, the cereblon ubiquitin ligase. Cereblon loss in zebrafish causes fin defects reminiscent of the limb defects seen in children exposed to thalidomide in utero. Here we show that lenalidomide-bound cereblon acquires the ability to target for proteasomal degradation two specific B cell transcription factors, Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3). Analysis of myeloma cell lines revealed that loss of IKZF1 and IKZF3 is both necessary and sufficient for lenalidomide's therapeutic effect, suggesting that the antitumor and teratogenic activities of thalidomide-like drugs are dissociable.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070318/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070318/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lu, Gang -- Middleton, Richard E -- Sun, Huahang -- Naniong, MarkVic -- Ott, Christopher J -- Mitsiades, Constantine S -- Wong, Kwok-Kin -- Bradner, James E -- Kaelin, William G Jr -- R01 CA068490/CA/NCI NIH HHS/ -- R01 CA076120/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Jan 17;343(6168):305-9. doi: 10.1126/science.1244917. Epub 2013 Nov 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24292623" target="_blank"〉PubMed〈/a〉
    Keywords: Antineoplastic Agents/*pharmacology ; Cell Line, Tumor ; HEK293 Cells ; Humans ; Ikaros Transcription Factor/genetics/*metabolism ; Multiple Myeloma/*metabolism ; Peptide Hydrolases/genetics/*metabolism ; Proteolysis ; Teratogens/*pharmacology ; Thalidomide/*analogs & derivatives/pharmacology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
    Location Call Number Expected Availability
    BibTip Others were also interested in ...
    PAPER CURRENT
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...