1. Novel route to chaetomellic acid A and analogues: serendipitous discovery of a more competent FTase inhibitor
Giuliano Fiscaletti, Andrew F Parsons, C Dale Poulter, Fulvia Felluga, Seoung-ryoung Choi, Franco Ghelfi, Fabrizio Roncaglia, Massimo Sabbatini, Franco Bellesia, Domenico Spinelli, Maria Cristina Menziani Bioorg Med Chem . 2013 Jan 1;21(1):348-58. doi: 10.1016/j.bmc.2012.10.034.
A new practical route to chaetomellic acid A (ACA), based on the copper catalysed radical cyclization (RC) of (Z)-3-(2,2-dichloropropanoyl)-2-pentadecylidene-1,3-thiazinane, is described. Remarkably, the process entailed: (i) a one-pot preparation of the intermediate N-α-perchloroacyl-2-(Z)-alkyliden-1,3-thiazinanes starting from N-(3-hydroxypropyl)palmitamide, (ii) a two step smooth transformation of the RC products into ACA and (iii) only one intermediate chromatographic purification step. The method offers a versatile approach to the preparation of ACA analogues, through the synthesis of an intermediate maleic anhydride with a vinylic group at the end of the aliphatic tail, a function that can be transformed through a thiol-ene coupling. Serendipitously, the disodium salt of 2-(9-(butylthio)nonyl)-3-methylmaleic acid, that we prepared as a representative sulfurated ACA analogue, was a more competent FTase inhibitor than ACA. This behaviour was analysed by a molecular docking study.
2. Farnesyltransferase and geranylgeranyltransferase I inhibitors in cancer therapy: important mechanistic and bench to bedside issues
A D Hamilton, S M Sebti Expert Opin Investig Drugs . 2000 Dec;9(12):2767-82. doi: 10.1517/13543784.9.12.2767.
The fact that proteins such as Ras, Rac and RhoA require farnesylation or geranylgeranylation to induce malignant transformation prompted many investigators to develop farnesyltransferase (FTase) and geranylgeranyltransferase I (GGTase I) inhibitors (FTIs and GGTIs, respectively) as novel anticancer drugs. Although FTIs have been shown to antagonise oncogenic signalling, reverse malignant transformation, inhibit human tumour growth in nude mice and induce tumour regression in transgenic mice without any signs of toxicity, their mechanism of action is not known. This review will focus on important mechanistic issues as well as bench to bedside translational issues. These will include the relevance to cancer therapy of the alternative geranylgeranylation of K-Ras when FTase is inhibited; a thorough discussion about evidence for and against the involvement of inhibition of prenylation of Ras and RhoB in the mechanism of FTIs' antitumour activity as well as effects of FTIs and GGTIs on the cell cycle machinery and the dynamics of bipolar spindle formation and chromosome alignment during mitosis. Bench to bedside issues relating to the design of hypothesis-driven clinical trials with biochemical correlates for proof-of-concept in man will also be discussed. This will include Phase I issues such as determining maximally tolerated dose (MTD) versus effective biological dose (EBD), as well as whether Phase II trials are still needed for clinical evaluations of anti-signalling agents. Other questions that will be addressed include: what levels of inhibition of FTase activity are required for tumour response in Phase II clinical evaluations? What FTase substrates are most relevant as biochemical correlates? Are signalling pathways such as H-Ras/PI3K/Akt and K-Ras/Raf/MEK/Erk significant biological readouts? Does Ras mutation status predict response? What are appropriate clinical end-points for FTI Phase II trials? For this latter important question, time to tumour progression, median survival, percentage of patients that progress, clinical benefits and improvement in quality of life will all be discussed.
3. Phase II and pharmacodynamic study of the farnesyltransferase inhibitor R115777 as initial therapy in patients with metastatic pancreatic adenocarcinoma
Steven J Cohen, James L Abbruzzese, R Katherine Alpaugh, Louis M Weiner, Nancy L Lewis, Susan McLaughlin, Tom Verhaeghe, Sulabha Ranganathan, Hao Wang, Neal J Meropol, Gary R Hudes, Amanda M Thistle, André Rogatko, Linus Ho, John J Wright, Juan J Perez-Ruixo, Mary Beard J Clin Oncol . 2003 Apr 1;21(7):1301-6. doi: 10.1200/JCO.2003.08.040.
Purpose:R115777 is a selective nonpeptidomimetic inhibitor of farnesyltransferase (FTase), one of several enzymes responsible for posttranslational modification that is required for the function of p21(ras) and other proteins. Given that RAS mutations are nearly universal in pancreatic cancer and R115777 demonstrated preclinical activity against pancreatic cell lines and xenografts, this phase II study was undertaken to determine its clinical activity and effect on target proteins in patients with measurable metastatic pancreatic adenocarcinoma.Patients and methods:Twenty patients who had not received prior therapy for metastatic disease were treated with 300 mg of R115777 orally every 12 hours for 21 of 28 days. Inhibition of FTase activity in peripheral-blood mononuclear cells was measured using a lamin B C-terminus peptide as substrate. Western blot analysis was performed to monitor farnesylation status of the chaperone protein HDJ-2.Results:No objective responses were seen. Median time to progression was 4.9 weeks, and median survival time was 19.7 weeks. The estimated 6-month survival rate was 25%, with no patients progression-free at 6 months. Grade 3/4 toxicities were liver enzyme elevation, anemia, neutropenia, thrombocytopenia, fatigue, nausea/vomiting, rash, and anorexia. FTase activity (mean +/- SD) decreased by 49.8% +/- 9.8% 4 hours after treatment on day 1 and 36.1% +/- 24.8% before treatment on day 15. HDJ-2 farnesylation (mean +/- SD) decreased by 33.4% +/- 19.8% on day 15.Conclusion:Although treatment with R115777 resulted in partial inhibition of FTase activity in mononuclear cells, it did not exhibit single-agent antitumor activity in patients with previously untreated metastatic pancreatic cancer.
