title: New derivatives of farnesylthiosalicylic acid (salirasib) for cancer treatment: farnesylthiosalicylamide inhibits tumor growth in nude mice models.
abstract: The Ras inhibitor S-trans,trans-farnesylthiosalicylic acid (FTS, Salirasib) interferes with Ras membrane interactions that are crucial for Ras-dependent transformation. It remains unknown whether modifications of the carboxyl group of FTS can affect its activity. Here we show that specific modifications of the FTS carboxyl group by esterification or amidation yield compounds with improved growth inhibitory activity, compared to FTS, as shown in Panc-1 and U87 cells. The most potent compounds were FTS-methoxymethyl ester and FTS-amide. However, selectivity toward active Ras-GTP, as known for FTS, was apparent with the amide derivatives of FTS. FTS-amide exhibited the overall highest efficacy in inhibition of Ras-GTP and cell growth. This new compound significantly inhibited growth of both Panc-1 tumors and U87 brain tumors. Thus amide derivatives of the FTS carboxyl group provide potent cell-growth inhibitors without loss of selectivity toward the active Ras protein and may serve as new candidates in cancer therapy.
authors.affiliation: Department of Neurobiology, The George S Wise Faculty of Life Sciences, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Goldberg
authors.forename: Roni
authors.initials: R
authors.lastname: Haklai
authors.forename: Victor
authors.initials: V
authors.lastname: Bauer
authors.forename: Aaron
authors.initials: A
authors.lastname: Heiss
authors.forename: Yoel
authors.initials: Y
authors.lastname: Kloog
mesh_terms: D000577:Amides / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005204:Farnesol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D012459:Salicylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D012459:Salicylates; C093323:farnesylthiosalicylic acid; D005204:Farnesol; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D015689:Oncogene Protein p21(ras)