1284544-59-7Relevant academic research and scientific papers
Structure guided design and kinetic analysis of highly potent benzimidazole inhibitors targeting the PDEδ prenyl binding site
Zimmermann, Gunther,Schultz-Fademrecht, Carsten,Küchler, Philipp,Murarka, Sandip,Ismail, Shehab,Triola, Gemma,Nussbaumer, Peter,Wittinghofer, Alfred,Waldmann, Herbert
supporting information, p. 5435 - 5448 (2014/07/08)
K-Ras is one of the most frequently mutated signal transducing human oncogenes. Ras signaling activity requires correct cellular localization of the GTPase. The spatial organization of K-Ras is controlled by the prenyl binding protein PDEδ, which enhances Ras diffusion in the cytosol. Inhibition of the Ras-PDEδ interaction by small molecules impairs Ras localization and signaling. Here we describe in detail the identification and structure guided development of Ras-PDEδ inhibitors targeting the farnesyl binding pocket of PDEδ with nanomolar affinity. We report kinetic data that characterize the binding of the most potent small molecule ligands to PDEδ and prove their binding to endogenous PDEδ in cell lysates. The PDEδ inhibitors provide promising starting points for the establishment of new drug discovery programs aimed at cancers harboring oncogenic K-Ras.
Benzimidazoles for the treatment of cancer
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Paragraph 0059-0060; 0079-0080; 0085-0086, (2014/03/22)
The present invention relates to novel substituted benzimidazoles and stereoisomeric forms, prodrugs, solvates, hydrates and/or pharmaceutically acceptable salts of these compounds as well as pharmaceutical compositions containing at least one of these substituted benzimidazoles together with pharmaceutically acceptable carrier, excipient and/or diluents. Said novel substituted benzimidazoles binding to the prenyl binding pocket of PDEδ have been identified as useful for the prophylaxis and treatment of cancer by the inhibition of the binding of PDEδ to K-Ras and of oncogenic Ras signalling in cells by altering its localization leading to cell death or inhibition of proliferation.
BENZIMIDAZOLES FOR THE TREATMENT OF CANCER
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Page/Page column 52; 57-58; 59, (2014/03/22)
The present invention relates to novel substituted benzimidazoles and stereoisomeric forms, prodrugs, solvates, hydrates and/or pharmaceutically acceptable salts of these compounds as well as pharmaceutical compositions containing at least one of these substituted benzimidazoles together with pharmaceutically acceptable carrier, excipient and/or diluents. Said novel substituted benzimidazoles binding to the prenyl binding pocket of PDEδ have been identified as useful for the prophylaxis and treatment of cancer by the inhibition of the binding of PDEδ to K-Ras and of oncogenic Ras signalling in cells by altering its localization leading to cell death or inhibition of proliferation.
