title: Recent progress in developing small molecule inhibitors designed to interfere with ras membrane association: toward inhibiting K-Ras and N-Ras functions.
abstract: K-Ras and N-Ras are mutated in a wide range of human cancers, thus making these proteins attractive targets of anticancer drug development. However, no effective compounds have been obtained so far. One of the approaches taken to inhibit the function of K-Ras and N-Ras is to interfere with their membrane association. Various attempts have been taken. In the first example, we examine the approach conceived in early 1990s to inhibit protein prenylation that is required for their membrane association. The initial premise that the inhibition of Ras farnesylation leads to the inhibition of Ras was not realized, mainly due to alternative prenylation of K-Ras and N-Ras proteins. This led to the idea that the combined inhibition of FTase and GGTase-I can block membrane association of K-Ras and N-Ras. Dual specificity inhibitors of FTase and GGTase-I (DPIs) were also developed. These compounds were tested in preclinical and clinical studies. It appears that sufficiently high concentration of the drug to inhibit K-Ras was not achieved in previous attempts. In addition, dose-limiting toxicity has been observed and this was primarily ascribed to GGTase-I inhibition. Strategies to confer cancer targeting capabilities to the inhibitors may overcome the dose-limiting toxicity. In the second approach, postprenylation events were exploited. This led to the development of various inhibitors including the ICMT inhibitors. Finally, recent identification of compounds that inhibit the interaction between K-Ras and PDE-δ is discussed.
authors.affiliation: Department of Microbiology, Immunology & Molecular Genetics, Jonsson Comprehensive Cancer Center, Molecular Biology Institute, University of California, Los Angeles, California, USA. Electronic address: fuyut@microbio.ucla.edu.
authors.forename: Fuyuhiko
authors.initials: F
authors.lastname: Tamanoi
authors.affiliation: Department of Microbiology, Immunology & Molecular Genetics, Jonsson Comprehensive Cancer Center, Molecular Biology Institute, University of California, Los Angeles, California, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017368:Protein Prenylation / Q000187:drug effects*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D054852:Small Molecule Libraries; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C117307:KRAS protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D054852:Small Molecule Libraries; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: DPI; Deltarasin; FTI; FTI/GGTI combination; GGTI; ICMT inhibitors; K-Ras and N-Ras; Membrane association