8 results on '"Ellis-Hutchings M"'
Search Results
2. Dual protein farnesyltransferase-geranylgeranyltransferase-I inhibitors as potential cancer chemotherapeutic agents.
- Author
-
deSolms SJ, Ciccarone TM, MacTough SC, Shaw AW, Buser CA, Ellis-Hutchings M, Fernandes C, Hamilton KA, Huber HE, Kohl NE, Lobell RB, Robinson RG, Tsou NN, Walsh ES, Graham SL, Beese LS, and Taylor JS
- Subjects
- Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Carrier Proteins metabolism, Crystallography, X-Ray, Drug Screening Assays, Antitumor, HSP40 Heat-Shock Proteins, Heat-Shock Proteins metabolism, Humans, Mice, Mice, Nude, Models, Molecular, Neoplasm Transplantation, Neoplasms, Experimental drug therapy, Protein Prenylation, Structure-Activity Relationship, Transplantation, Heterologous, Tumor Cells, Cultured, rap1 GTP-Binding Proteins metabolism, ras Proteins metabolism, Alkyl and Aryl Transferases antagonists & inhibitors, Antineoplastic Agents chemical synthesis
- Abstract
A series of novel diaryl ether lactams have been identified as very potent dual inhibitors of protein farnesyltransferase (FTase) and protein geranylgeranyltransferase I (GGTase-I), enzymes involved in the prenylation of Ras. The structure of the complex formed between one of these compounds and FTase has been determined by X-ray crystallography. These compounds are the first reported to inhibit the prenylation of the important oncogene Ki-Ras4B in vivo. Unfortunately, doses sufficient to achieve this endpoint were rapidly lethal.
- Published
- 2003
- Full Text
- View/download PDF
3. The synthesis and biological evaluation of a series of potent dual inhibitors of farnesyl and geranyl-Geranyl protein transferases.
- Author
-
Tucker TJ, Abrams MT, Buser CA, Davide JP, Ellis-Hutchings M, Fernandes C, Gibbs JB, Graham SL, Hartman GD, Huber HE, Liu D, Lobell RB, Lumma WC, Robinson RG, Sisko JT, and Smith AM
- Subjects
- Binding Sites, Binding, Competitive, Inhibitory Concentration 50, Protein Binding, Structure-Activity Relationship, Tumor Cells, Cultured, rap GTP-Binding Proteins drug effects, rap GTP-Binding Proteins metabolism, Alkyl and Aryl Transferases antagonists & inhibitors, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology
- Abstract
We have prepared a series of potent, dual inhibitors of the prenyl transferases farnesyl protein transferase (FPTase) and geranyl-geranyl protein transferase I (GGPTase). The compounds were shown to possess potent activity against both enzymes in cell culture. Mechanistic analysis has shown that the compounds are CAAX competitive for FPTase inhibition but geranyl-geranyl pyrophosphate (GGPP) competitive for GGPTase inhibiton.
- Published
- 2002
- Full Text
- View/download PDF
4. 3-Aminopyrrolidinone farnesyltransferase inhibitors: design of macrocyclic compounds with improved pharmacokinetics and excellent cell potency.
- Author
-
Bell IM, Gallicchio SN, Abrams M, Beese LS, Beshore DC, Bhimnathwala H, Bogusky MJ, Buser CA, Culberson JC, Davide J, Ellis-Hutchings M, Fernandes C, Gibbs JB, Graham SL, Hamilton KA, Hartman GD, Heimbrook DC, Homnick CF, Huber HE, Huff JR, Kassahun K, Koblan KS, Kohl NE, Lobell RB, Lynch JJ Jr, Robinson R, Rodrigues AD, Taylor JS, Walsh ES, Williams TM, and Zartman CB
- Subjects
- Animals, Cell Line, Chromatography, Liquid, Crystallography, X-Ray, Cytochrome P-450 CYP3A, Cytochrome P-450 Enzyme Inhibitors, Dogs, ERG1 Potassium Channel, Electrocardiography, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacokinetics, Ether-A-Go-Go Potassium Channels, Farnesyltranstransferase, Humans, In Vitro Techniques, Magnetic Resonance Spectroscopy, Mass Spectrometry, Microsomes, Liver drug effects, Microsomes, Liver enzymology, Models, Molecular, Molecular Structure, Naphthalenes chemistry, Naphthalenes pharmacokinetics, Oxidoreductases, N-Demethylating antagonists & inhibitors, Potassium Channels metabolism, Protein Binding, Pyrrolidines chemistry, Pyrrolidines pharmacokinetics, Stereoisomerism, Structure-Activity Relationship, Transcriptional Regulator ERG, Alkyl and Aryl Transferases antagonists & inhibitors, Aryl Hydrocarbon Hydroxylases, Cation Transport Proteins, DNA-Binding Proteins, Enzyme Inhibitors chemical synthesis, Naphthalenes chemical synthesis, Potassium Channels, Voltage-Gated, Pyrrolidines chemical synthesis, Trans-Activators
- Abstract
A series of macrocyclic 3-aminopyrrolidinone farnesyltransferase inhibitors (FTIs) has been synthesized. Compared with previously described linear 3-aminopyrrolidinone FTIs such as compound 1, macrocycles such as 49 combined improved pharmacokinetic properties with a reduced potential for side effects. In dogs, oral bioavailability was good to excellent, and increases in plasma half-life were due to attenuated clearance. It was observed that in vivo clearance correlated with the flexibility of the molecules and this concept proved useful in the design of FTIs that exhibited low clearance, such as FTI 78. X-ray crystal structures of compounds 49 and 66 complexed with farnesyltransferase (FTase)-farnesyl diphosphate (FPP) were determined, and they provide details of the key interactions in such ternary complexes. Optimization of this 3-aminopyrrolidinone series of compounds led to significant increases in potency, providing 83 and 85, the most potent inhibitors of FTase in cells described to date.
- Published
- 2002
- Full Text
- View/download PDF
5. Potent inhibitors of farnesyltransferase and geranylgeranyltransferase-I.
- Author
-
Nguyen DN, Stump CA, Walsh ES, Fernandes C, Davide JP, Ellis-Hutchings M, Robinson RG, Williams TM, Lobell RB, Huber HE, and Buser CA
- Subjects
- Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Alkyl and Aryl Transferases antagonists & inhibitors, Enzyme Inhibitors pharmacology
- Abstract
Compound 1 has been shown to be a dual prenylation inhibitor with FPTase (IC50=2 nM) and GGPTase-I (IC50=95 nM). Analogues of 1, which replaced the cyanophenyl group with various biaryls, led to the discovery of highly potent dual FPTase/GGPTase-I inhibitors. 4-trifluoromethylphenyl, trifluoropentynyl, and trifluoropentyl were identified as good p-cyano replacements.
- Published
- 2002
- Full Text
- View/download PDF
6. Evaluation of farnesyl:protein transferase and geranylgeranyl:protein transferase inhibitor combinations in preclinical models.
- Author
-
Lobell RB, Omer CA, Abrams MT, Bhimnathwala HG, Brucker MJ, Buser CA, Davide JP, deSolms SJ, Dinsmore CJ, Ellis-Hutchings MS, Kral AM, Liu D, Lumma WC, Machotka SV, Rands E, Williams TM, Graham SL, Hartman GD, Oliff AI, Heimbrook DC, and Kohl NE
- Subjects
- Alkyl and Aryl Transferases metabolism, Animals, Antineoplastic Combined Chemotherapy Protocols toxicity, Apoptosis drug effects, Apoptosis physiology, Drug Screening Assays, Antitumor, Drug Synergism, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors toxicity, Farnesyltranstransferase, Female, Humans, Mice, Mice, Nude, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms enzymology, Pancreatic Neoplasms pathology, Protein Prenylation drug effects, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, ras Proteins metabolism, Alkyl and Aryl Transferases antagonists & inhibitors, Antineoplastic Combined Chemotherapy Protocols pharmacology, Enzyme Inhibitors pharmacology
- Abstract
Farnesyl:protein transferase (FPTase) inhibitors (FTIs) were originally developed as potential anticancer agents targeting the ras oncogene and are currently in clinical trials. Whereas FTIs inhibit the farnesylation of Ha-Ras, they do not completely inhibit the prenylation of Ki-Ras, the allele most frequently mutated in human cancers. Whereas farnesylation of Ki-Ras is blocked by FTIs, Ki-Ras remains prenylated in FTI-treated cells because of its modification by the related prenyltransferase, geranylgeranyl:protein transferase type I (GGPTase-I). Hence, cells transformed with Ki-ras tend to be more resistant to FTIs than Ha-ras-transformed cells. To determine whether Ki-ras-transformed cells can be targeted by combining an FTI with a GGPTase-I inhibitor (GGTI), we evaluated potent, selective FTIs, GGTIs, and dual prenylation inhibitors (DPIs) that have both FTI and GGTI activity. We find that in human PSN-1 pancreatic tumor cells, which harbor oncogenic Ki-ras, and in other tumor lines having either wild-type or oncogenic Ki-ras, treatment with an FTI/GGTI combination or with a DPI blocks Ki-Ras prenylation and induces markedly higher levels of apoptosis relative to FTI or GGTI alone. We demonstrate that these compounds can inhibit their enzyme targets in mice by monitoring pancreatic and tumor tissues from treated animals for inhibition of prenylation of Ki-Ras, HDJ2, a substrate specific for FPTase, and Rap1A, a substrate specific for GGPTase-I. Continuous infusion (72 h) of varying doses of GGTI in conjunction with a high, fixed dose of FTI causes a dose-dependent inhibition of Ki-Ras prenylation. However, a 72-h infusion of a GGTI, at a dose sufficient to inhibit Ki-Ras prenylation in the presence of an FTI, causes death within 2 weeks of the infusion when administered either as monotherapy or in combination with an FTI. DPIs are also lethal after a 72-h infusion at doses that inhibit Ki-Ras prenylation. Because 24 h infusion of a high dose of DPI is tolerated and inhibits Ki-Ras prenylation, we compared the antitumor efficacy from a 24-h FTI infusion to that of a DPI in a nude mouse/PSN-1 tumor cell xenograft model and in Ki-ras transgenic mice with mammary tumors. The FTI and DPI were dosed at a level that provided comparable inhibition of FPTase. The FTI and the DPI displayed comparable efficacy, causing a decrease in growth rate of the PSN-1 xenograft tumors and tumor regression in the transgenic model, but neither treatment regimen induced a statistically significant increase in tumor cell apoptosis. Although FTI/GGTI combinations elicit a greater apoptotic response than either agent alone in vitro, the toxicity associated with GGTI treatment in vivo limits the duration of treatment and, thus, may limit the therapeutic benefit that might be gained by inhibiting oncogenic Ki-Ras through dual prenyltransferase inhibitor therapy.
- Published
- 2001
7. Design and biological activity of (S)-4-(5-([1-(3-chlorobenzyl)-2-oxopyrrolidin-3-ylamino]methyl)imidazol-1-ylmethyl)benzonitrile, a 3-aminopyrrolidinone farnesyltransferase inhibitor with excellent cell potency.
- Author
-
Bell IM, Gallicchio SN, Abrams M, Beshore DC, Buser CA, Culberson JC, Davide J, Ellis-Hutchings M, Fernandes C, Gibbs JB, Graham SL, Hartman GD, Heimbrook DC, Homnick CF, Huff JR, Kassahun K, Koblan KS, Kohl NE, Lobell RB, Lynch JJ Jr, Miller PA, Omer CA, Rodrigues AD, Walsh ES, and Williams TM
- Subjects
- Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Binding Sites, Binding, Competitive, Biological Availability, Cell Line, Transformed, Dogs, Drug Design, Drug Screening Assays, Antitumor, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Farnesyltranstransferase, Genes, ras, Imidazoles chemistry, Imidazoles pharmacology, Lactams chemistry, Lactams pharmacology, Mice, Mice, Transgenic, Models, Molecular, Neoplasms, Experimental pathology, Nitriles chemistry, Nitriles pharmacology, Pyrrolidinones chemistry, Pyrrolidinones pharmacology, Radioligand Assay, Stereoisomerism, Structure-Activity Relationship, Alkyl and Aryl Transferases antagonists & inhibitors, Antineoplastic Agents chemical synthesis, Enzyme Inhibitors chemical synthesis, Imidazoles chemical synthesis, Lactams chemical synthesis, Nitriles chemical synthesis, Pyrrolidinones chemical synthesis
- Abstract
The synthesis, structure-activity relationships, and biological properties of a novel series of imidazole-containing inhibitors of farnesyltransferase are described. Starting from a 3-aminopyrrolidinone core, a systematic series of modifications provided 5h, a non-thiol, non-peptide farnesyltransferase inhibitor with excellent bioavailability in dogs. Compound 5h was found to have an unusually favorable ratio of cell potency to intrinsic potency, compared with other known FTIs. It exhibited excellent potency against a range of tumor cell lines in vitro and showed full efficacy in the K-rasB transgenic mouse model.
- Published
- 2001
- Full Text
- View/download PDF
8. Evaluation of amino acid-based linkers in potent macrocyclic inhibitors of farnesyl-protein transferase.
- Author
-
Beshore DC, Bell IM, Dinsmore CJ, Homnick CF, Culberson JC, Robinson RG, Fernandes C, Walsh ES, Abrams MT, Bhimnathwala HG, Davide JP, Ellis-Hutchings MS, Huber HA, Koblan KS, Buser CA, Kohl NE, Lobell RB, Chen IW, McLoughlin DA, Olah TV, Graham SL, Hartman GD, and Williams TM
- Subjects
- Amino Acids chemistry, Animals, Cells, Cultured, Dogs, Enzyme Inhibitors chemical synthesis, Half-Life, Inhibitory Concentration 50, Metabolic Clearance Rate physiology, Molecular Conformation, Protein Binding drug effects, Rats, Alkyl and Aryl Transferases antagonists & inhibitors, Alkyl and Aryl Transferases drug effects, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors pharmacokinetics
- Abstract
A series of amino acid-based linkers was used to investigate the effects of various substituents upon the potency, pharmacokinetic properties, and conformation of macrocyclic farnesyl-protein transferase inhibitors (FTIs). As a result of the studies described herein, highly potent FTIs with improved pharmacokinetic profiles have been identified.
- Published
- 2001
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.