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  • 1
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    Small molecule inhibition of the KRAS-PDEdelta interaction impairs oncogenic KRAS signalling (2013)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2013-05-24
    Description: The KRAS oncogene product is considered a major target in anticancer drug discovery. However, direct interference with KRAS signalling has not yet led to clinically useful drugs. Correct localization and signalling by farnesylated KRAS is regulated by the prenyl-binding protein PDEdelta, which sustains the spatial organization of KRAS by facilitating its diffusion in the cytoplasm. Here we report that interfering with binding of mammalian PDEdelta to KRAS by means of small molecules provides a novel opportunity to suppress oncogenic RAS signalling by altering its localization to endomembranes. Biochemical screening and subsequent structure-based hit optimization yielded inhibitors of the KRAS-PDEdelta interaction that selectively bind to the prenyl-binding pocket of PDEdelta with nanomolar affinity, inhibit oncogenic RAS signalling and suppress in vitro and in vivo proliferation of human pancreatic ductal adenocarcinoma cells that are dependent on oncogenic KRAS. Our findings may inspire novel drug discovery efforts aimed at the development of drugs targeting oncogenic RAS.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zimmermann, Gunther -- Papke, Bjorn -- Ismail, Shehab -- Vartak, Nachiket -- Chandra, Anchal -- Hoffmann, Maike -- Hahn, Stephan A -- Triola, Gemma -- Wittinghofer, Alfred -- Bastiaens, Philippe I H -- Waldmann, Herbert -- England -- Nature. 2013 May 30;497(7451):638-42. doi: 10.1038/nature12205. Epub 2013 May 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemical Biology, Max Planck Institute of Molecular Physiology, D-44227 Dortmund, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23698361" target="_blank"〉PubMed〈/a〉
    Keywords: Adenocarcinoma/drug therapy/genetics/metabolism ; Animals ; Benzimidazoles/*chemistry/metabolism/*pharmacology/therapeutic use ; Binding Sites ; Carcinoma, Pancreatic Ductal/drug therapy/genetics/metabolism ; Cell Line ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cyclic Nucleotide Phosphodiesterases, Type 6/antagonists & ; inhibitors/chemistry/*metabolism ; Dogs ; Humans ; Hydrogen Bonding ; MAP Kinase Signaling System/drug effects ; Mice ; Mice, Nude ; Mitogen-Activated Protein Kinases/metabolism ; Models, Molecular ; Molecular Conformation ; Neoplasm Transplantation ; Oncogene Protein p21(ras)/*antagonists & inhibitors/genetics/*metabolism ; Protein Binding/drug effects ; Signal Transduction/*drug effects
    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)
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  • 2
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    DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1 (1996)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1996-01-19
    Description: About 90 percent of human pancreatic carcinomas show allelic loss at chromosome 18q. To identify candidate tumor suppressor genes on 18q, a panel of pancreatic carcinomas were analyzed for convergent sites of homozygous deletion. Twenty-five of 84 tumors had homozygous deletions at 18q21.1, a site that excludes DCC (a candidate suppressor gene for colorectal cancer) and includes DPC4, a gene similar in sequence to a Drosophila melanogaster gene (Mad) implicated in a transforming growth factor-beta (TGF-beta)-like signaling pathway. Potentially inactivating mutations in DPC4 were identified in six of 27 pancreatic carcinomas that did not have homozygous deletions at 18q21.1. These results identify DPC4 as a candidate tumor suppressor gene whose inactivation may play a role in pancreatic and possibly other human cancers.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hahn, S A -- Schutte, M -- Hoque, A T -- Moskaluk, C A -- da Costa, L T -- Rozenblum, E -- Weinstein, C L -- Fischer, A -- Yeo, C J -- Hruban, R H -- Kern, S E -- CA62924/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 1996 Jan 19;271(5247):350-3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/8553070" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Amino Acid Sequence ; Animals ; Base Sequence ; Cell Division ; Chromosome Mapping ; *Chromosomes, Human, Pair 18 ; *DNA-Binding Proteins ; Gene Deletion ; Gene Expression ; *Genes, Tumor Suppressor ; Genetic Markers ; Humans ; Mice ; Molecular Sequence Data ; Mutation ; Neoplasm Transplantation ; Pancreatic Neoplasms/*genetics/pathology ; Proteins/chemistry/*genetics/physiology ; Signal Transduction ; Smad4 Protein ; *Trans-Activators ; Transforming Growth Factor beta/physiology ; Transplantation, Heterologous ; Tumor Cells, Cultured
    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)
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