Charles Omer - Academia.edu (original) (raw)
Papers by Charles Omer
Cell growth & differentiation: the molecular biology journal of the American Association for Cancer Research
The Ras oncoprotein must be modified by farnesyl transferase (FTase) for biological activity. The... more The Ras oncoprotein must be modified by farnesyl transferase (FTase) for biological activity. Therefore, inhibition of FTase may offer a means to block ras induced cell transformation. To address this hypothesis, we have introduced antisense and dominant inhibitory FTase expression plasmids into a panel of normal, mutant ras-, and mos- transformed rodent fibroblasts in an effort to genetically suppress FTase activity. Antisense FTase constructs reduced colony formation efficiency approximately 29% in normal and approximately 41% in ras-transformed cells relative to control plasmids. In contrast, antisense FTase plasmids did not exhibit a statistically significant effect on colony formation efficiency in mos-transformed transfectants. FTase alpha N199K is a mutant form of the alpha subunit of FTase that exhibits dominant inhibitory activity versus native FTase. Only mos-transformed transfectants exhibited expression of alpha N199K RNA in 15 of 16 fibroblast lines that were randomly selected and characterized. Our data suggest that genetic inhibition of FTase may result in a selection against animal cell growth.
Methods in Enzymology, 1995
ABSTRACT
Cancer research, Jan 15, 2001
Farnesyl:protein transferase (FPTase) inhibitors (FTIs) were originally developed as potential an... more 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 ...
Molecular and cellular biology, 1998
The farnesyltransferase inhibitor L-744,832 selectively blocks the transformed phenotype of cultu... more The farnesyltransferase inhibitor L-744,832 selectively blocks the transformed phenotype of cultured cells expressing a mutated H-ras gene and induces dramatic regression of mammary and salivary carcinomas in mouse mammary tumor virus (MMTV)-v-Ha-ras transgenic mice. To better understand how the farnesyltransferase inhibitors might be used in the treatment of human tumors, we have further explored the mechanisms by which L-744,832 induces tumor regression in a variety of transgenic mouse tumor models. We assessed whether L-744,832 induces apoptosis or alterations in cell cycle distribution and found that the tumor regression in MMTV-v-Ha-ras mice could be attributed entirely to elevation of apoptosis levels. In contrast, treatment with doxorubicin, which induces apoptosis in many tumor types, had a minimal effect on apoptosis in these tumors and resulted in a less dramatic tumor response. To determine whether functional p53 is required for L-744,832-induced apoptosis and the resulta...
Biochemical Society transactions, 1996
Journal of Medicinal Chemistry, 1996
Mutations in the ras oncogene are present in many human cancers, including 30−50% of colon and 90... more Mutations in the ras oncogene are present in many human cancers, including 30−50% of colon and 90% of pancreatic cancer. 1,2 The Ras protein undergoes a series of post-translational modifications, including S-farnesylation of a cysteine residue located in the C-terminal ...
Transmembrane Signaling Protocols, 1998
The methods outlined in Subheading 3. provide a logical sequence of assays with which to evaluate... more The methods outlined in Subheading 3. provide a logical sequence of assays with which to evaluate the biochemical and biological properties of potential FPTase inhibitors. The clinical predictability of these assays must await the evaluation of one or more of these compounds in humans.
Trends in Pharmacological Sciences, 1997
For Ras oncoproteins to transform mammalian cells, they must be post-translationally farnesylated... more For Ras oncoproteins to transform mammalian cells, they must be post-translationally farnesylated in a reaction catalysed by the enzyme farnesyl-protein transferase (FPTase). Inhibitors of FPTase have therefore been proposed as anti-cancer agents. In this review Charles Omer and Nancy Kohl discuss the development of FPTase inhibitors that are kinetically competitive with the protein substrate in the farnesylation reaction. These compounds are potent and selective inhibitors of the enzyme that block the tumourigenic phenotypes of ras-transformed cells and human tumour cells in cell culture and in animal models.
Protein Science, 2008
Farnesyl-protein transferase (FPTase) catalyzes the posttranslational farnesylation of the cystei... more Farnesyl-protein transferase (FPTase) catalyzes the posttranslational farnesylation of the cysteine residue located in the carboxyl-terminal tetrapeptide of the Ras oncoprotein. Prenylation of this residue is essential for the membrane association and cell-transforming activities of ras. Inhibitors of FPTase have been demonstrated to inhibit ras-dependent cell transformation and thus represent a potential therapeutic strategy for the treatment of human cancers. The FPTase-bound conformation of a tetrapeptide inhibitor, CVWM, and a novel pseudopeptide inhibitor, L-739,787, have been determined by NMR spectroscopy. Distance constraints were derived from twodimensional transferred nuclear Overhauser effect experiments. Ligand competition experiments identified the NOES that originate from the active-site conformation. Structures were calculated with the combination of distance geometry and restrained energy minimization. Both peptide backbones are shown to adopt nonideal reverseturn conformations most closely approximating a type 111 P-turn. These results provide a basis for understanding the spatial arrangements necessary for inhibitor binding and selectivity and may aid in the design of therapeutic agents.
Nature Medicine, 1995
For Ras oncoproteins to transform mammalian cells, they must be post-translationally modified wit... more For Ras oncoproteins to transform mammalian cells, they must be post-translationally modified with a farnesyl group in a reaction catalysed by the enzyme farnesyl-protein transferase (FPTase). Inhibitors of FPTase have therefore been proposed as anti-cancer agents. We show that L-744,832, which mimics the CaaX motif to which the farnesyl group is added, is a potent and selective inhibitor of FPTase. In MMTV-v-Ha-ras mice bearing palpable tumours, daily administration of L-744,832 caused tumour regression. Following cessation of treatment, tumours reappeared, the majority of which regressed upon retreatment. No systemic toxicity was found upon necropsy of L-744,832-treated mice. This first demonstration of anti-FPTase-mediated tumour regression suggests that FPTase inhibitors may be safe and effective anti-tumour agents in some cancers.
Molecular Microbiology, 1994
Modification of proteins at C-terminal cysteine residue(s) by the isoprenoids farnesyl (C15) and ... more Modification of proteins at C-terminal cysteine residue(s) by the isoprenoids farnesyl (C15) and geranylgeranyl (C20) is essential for the biological function of a number of eukaryotic proteins including fungal mating factors and the small, GTP-binding proteins of the Ras superfamily. Three distinct enzymes, conserved between yeast and mammals, have been identified that prenylate proteins: farnesyl protein transferase, geranylgeranyl protein transferase type I and geranylgeranyl protein transferase type II. Each prenyl protein transferase has its own protein substrate specificity. Much has been learned about the biology, genetics and biochemistry of protein prenylation and prenyl protein transferases through studies of eukaryotic microorganisms, particularly Saccharomyces cerevisiae. The functional importance of protein prenylation was first demonstrated with fungal mating factors. The initial genetic analysis of prenyl protein transferases was in S. cerevisiae with the isolation and subsequent characterization of mutations in the RAM1, RAM2, CDC43 and BET2 genes, each of which encodes a prenyl protein transferase subunit. We review here these and other studies on protein prenylation in eukaryotic microbes and how they relate to and have contributed to our knowledge about protein prenylation in all eukaryotic cells.
Journal of Medicinal Chemistry, 2007
A new series of MEK1 inhibitors, the 4-anilino-5-carboxamido-2-pyridones, were designed and synth... more A new series of MEK1 inhibitors, the 4-anilino-5-carboxamido-2-pyridones, were designed and synthesized using a combination of medicinal chemistry, computational chemistry, and structural elucidation. The effect of variation in the carboxamide side chain, substitution on the pyridone nitrogen, and replacement of the 4'-iodide were all investigated. This study afforded several compounds which were either equipotent or more potent than the clinical candidate CI-1040 (1) in an isolated enzyme assay, as well as murine colon carcinoma (C26) cells, as measured by suppression of phosphorylated ERK substrate. Most notably, pyridone 27 was found to be more potent than 1 in vitro and produced a 100% response rate at a lower dose than 1, when tested for in vivo efficacy in animals bearing C26 tumors.
Journal of Medicinal Chemistry, 2001
The synthesis, structure-activity relationships, and biological properties of a novel series of i... more 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.
Journal of Biological Chemistry, 1997
The roles of 11 conserved amino acids of the beta-subunit of human farnesyl:protein transferase (... more The roles of 11 conserved amino acids of the beta-subunit of human farnesyl:protein transferase (FTase) were examined by performing kinetic and biochemical analyses of site-directed mutants. This biochemical information along with the x-ray crystal structure of rat FTase indicates that residues His-248, Arg-291, Lys-294, and Trp-303 are involved with binding and utilization of the substrate farnesyl diphosphate. Our data confirm structural evidence that amino acids Cys-299, Asp-297, and His-362 are ligands for the essential Zn2+ ion and suggest that Asp-359 may also play a role in Zn2+ binding. Additionally, we demonstrate that Arg-202 is important for binding the essential C-terminal carboxylate of the protein substrate.
Current Opinion in Chemical Biology, 1997
Over the past few years, the idea that farnesyl-protein transferase (FPTase) inhibitors might be ... more Over the past few years, the idea that farnesyl-protein transferase (FPTase) inhibitors might be effective antiproliferativelantitumor agents has been realized in studies of cultured cells and in rodent models of cancer. Most of the studies with FPTase inhibitors have focused on inhibiting the growth of ras-transformed cells in vitro or the growth of ras-dependent tumors in mice. More recently, it has been recognized that the antiproliferative effect of FPTase inhibitors may extend beyond ras-driven tumors. It now seems likely that the ability of FPTase inhibitors to reverse the malignant phenotype results, at least in part, from inhibiting the farnesylation of proteins other than Ras. Addresses Boyartchuk VL, Ashby MN, Rine J: Modulation of Ras and afactor function by carboxyl-terminal proteolysis. Science 1997, 275:1796-l 600. First molecular characterization of a CaaX protease. Genetic inhibition of the protease inhibited Ras function in yeast but was not toxic to the yeast. This work should lead to the cloning of mammalian CaaX protease, which is a potential target for the development of inhibitors with anti-Ras activity. 9. Clarke S: Protein isoprenylation and methylation at carboxylterminal cysteine residues. Annu Rev Biochem 1992, 61:355-386. 10. Dudler T, Gelb MH: Palmitoylation of Ha-Ras facilitates membrane binding, activation of downstream effecters. and meiotic maturation in Xenopus oocytes. J Biol Chem 1996, 271 :11541-l 1547. Farnesyltransferase inhibitors versus Ras inhibitors Gibbs et a/. 203 22. James GL, Goldstein JL, Brown MS: Polylysine and CVIM sequences of K-RasB dictate specificity of prenylation and confer resistance to benzodiazepine peptidomimetic in vitro. J Biol Chem 1995, 270:6221-6226. 23. Rowell CA, Kowalczyk JJ, Lewis MD, Garcia AM: Direct . . demonstration of geranylgeranylation and farnesylation of Ki-Ras in Go. J Biol Chem 1997, 272:14093-l 4097. Please see annotation I1 5.01.
Breast Cancer Research and Treatment, 1996
The oncoprotein encoded by mutant ras genes is initially synthesized as a cytoplasmic precursor w... more The oncoprotein encoded by mutant ras genes is initially synthesized as a cytoplasmic precursor which requires posttranslational processing to attain biological activity; farnesylation of the cysteine residue present in the CaaX motif located at the carboxy-terminus of all Ras proteins is ...
Bioorganic & Medicinal Chemistry Letters, 2011
Bioorganic & Medicinal Chemistry Letters, 2009
3-Amido-4-anilinoquinolines are potent and highly selective inhibitors of CSF-1R. Their synthesis... more 3-Amido-4-anilinoquinolines are potent and highly selective inhibitors of CSF-1R. Their synthesis and SAR is reported, along with initial efforts to optimize the physical properties and PK through modifications at the quinoline 6-and 7-positions.
Bioorganic & Medicinal Chemistry Letters, 2009
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / b m c l in our ce... more j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / b m c l in our cell assay (4.2 lM). The 2,3-Cl example 11 was closer to the level of potency we felt was required (0.44 lM in the cell), but still significantly less active than the corresponding 7-MeO compound 5.
Bioorganic & Medicinal Chemistry Letters, 2013
The potent and selective 3-amido-4-anilinoquinoline CSF-1R inhibitor AZ683 suffered from cardiova... more The potent and selective 3-amido-4-anilinoquinoline CSF-1R inhibitor AZ683 suffered from cardiovascular liabilities, which were linked to the off-target activities of the compound and ion channel activity in particular. Less basic and less lipophilic examples from both the quinoline and cinnoline series demonstrated cleaner secondary pharmacology profiles. Cinnoline 31 retained the required potency and oral PK profile, and was progressed through the safety screening cascade to be nominated into development as AZD7507.
Cell growth & differentiation: the molecular biology journal of the American Association for Cancer Research
The Ras oncoprotein must be modified by farnesyl transferase (FTase) for biological activity. The... more The Ras oncoprotein must be modified by farnesyl transferase (FTase) for biological activity. Therefore, inhibition of FTase may offer a means to block ras induced cell transformation. To address this hypothesis, we have introduced antisense and dominant inhibitory FTase expression plasmids into a panel of normal, mutant ras-, and mos- transformed rodent fibroblasts in an effort to genetically suppress FTase activity. Antisense FTase constructs reduced colony formation efficiency approximately 29% in normal and approximately 41% in ras-transformed cells relative to control plasmids. In contrast, antisense FTase plasmids did not exhibit a statistically significant effect on colony formation efficiency in mos-transformed transfectants. FTase alpha N199K is a mutant form of the alpha subunit of FTase that exhibits dominant inhibitory activity versus native FTase. Only mos-transformed transfectants exhibited expression of alpha N199K RNA in 15 of 16 fibroblast lines that were randomly selected and characterized. Our data suggest that genetic inhibition of FTase may result in a selection against animal cell growth.
Methods in Enzymology, 1995
ABSTRACT
Cancer research, Jan 15, 2001
Farnesyl:protein transferase (FPTase) inhibitors (FTIs) were originally developed as potential an... more 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 ...
Molecular and cellular biology, 1998
The farnesyltransferase inhibitor L-744,832 selectively blocks the transformed phenotype of cultu... more The farnesyltransferase inhibitor L-744,832 selectively blocks the transformed phenotype of cultured cells expressing a mutated H-ras gene and induces dramatic regression of mammary and salivary carcinomas in mouse mammary tumor virus (MMTV)-v-Ha-ras transgenic mice. To better understand how the farnesyltransferase inhibitors might be used in the treatment of human tumors, we have further explored the mechanisms by which L-744,832 induces tumor regression in a variety of transgenic mouse tumor models. We assessed whether L-744,832 induces apoptosis or alterations in cell cycle distribution and found that the tumor regression in MMTV-v-Ha-ras mice could be attributed entirely to elevation of apoptosis levels. In contrast, treatment with doxorubicin, which induces apoptosis in many tumor types, had a minimal effect on apoptosis in these tumors and resulted in a less dramatic tumor response. To determine whether functional p53 is required for L-744,832-induced apoptosis and the resulta...
Biochemical Society transactions, 1996
Journal of Medicinal Chemistry, 1996
Mutations in the ras oncogene are present in many human cancers, including 30−50% of colon and 90... more Mutations in the ras oncogene are present in many human cancers, including 30−50% of colon and 90% of pancreatic cancer. 1,2 The Ras protein undergoes a series of post-translational modifications, including S-farnesylation of a cysteine residue located in the C-terminal ...
Transmembrane Signaling Protocols, 1998
The methods outlined in Subheading 3. provide a logical sequence of assays with which to evaluate... more The methods outlined in Subheading 3. provide a logical sequence of assays with which to evaluate the biochemical and biological properties of potential FPTase inhibitors. The clinical predictability of these assays must await the evaluation of one or more of these compounds in humans.
Trends in Pharmacological Sciences, 1997
For Ras oncoproteins to transform mammalian cells, they must be post-translationally farnesylated... more For Ras oncoproteins to transform mammalian cells, they must be post-translationally farnesylated in a reaction catalysed by the enzyme farnesyl-protein transferase (FPTase). Inhibitors of FPTase have therefore been proposed as anti-cancer agents. In this review Charles Omer and Nancy Kohl discuss the development of FPTase inhibitors that are kinetically competitive with the protein substrate in the farnesylation reaction. These compounds are potent and selective inhibitors of the enzyme that block the tumourigenic phenotypes of ras-transformed cells and human tumour cells in cell culture and in animal models.
Protein Science, 2008
Farnesyl-protein transferase (FPTase) catalyzes the posttranslational farnesylation of the cystei... more Farnesyl-protein transferase (FPTase) catalyzes the posttranslational farnesylation of the cysteine residue located in the carboxyl-terminal tetrapeptide of the Ras oncoprotein. Prenylation of this residue is essential for the membrane association and cell-transforming activities of ras. Inhibitors of FPTase have been demonstrated to inhibit ras-dependent cell transformation and thus represent a potential therapeutic strategy for the treatment of human cancers. The FPTase-bound conformation of a tetrapeptide inhibitor, CVWM, and a novel pseudopeptide inhibitor, L-739,787, have been determined by NMR spectroscopy. Distance constraints were derived from twodimensional transferred nuclear Overhauser effect experiments. Ligand competition experiments identified the NOES that originate from the active-site conformation. Structures were calculated with the combination of distance geometry and restrained energy minimization. Both peptide backbones are shown to adopt nonideal reverseturn conformations most closely approximating a type 111 P-turn. These results provide a basis for understanding the spatial arrangements necessary for inhibitor binding and selectivity and may aid in the design of therapeutic agents.
Nature Medicine, 1995
For Ras oncoproteins to transform mammalian cells, they must be post-translationally modified wit... more For Ras oncoproteins to transform mammalian cells, they must be post-translationally modified with a farnesyl group in a reaction catalysed by the enzyme farnesyl-protein transferase (FPTase). Inhibitors of FPTase have therefore been proposed as anti-cancer agents. We show that L-744,832, which mimics the CaaX motif to which the farnesyl group is added, is a potent and selective inhibitor of FPTase. In MMTV-v-Ha-ras mice bearing palpable tumours, daily administration of L-744,832 caused tumour regression. Following cessation of treatment, tumours reappeared, the majority of which regressed upon retreatment. No systemic toxicity was found upon necropsy of L-744,832-treated mice. This first demonstration of anti-FPTase-mediated tumour regression suggests that FPTase inhibitors may be safe and effective anti-tumour agents in some cancers.
Molecular Microbiology, 1994
Modification of proteins at C-terminal cysteine residue(s) by the isoprenoids farnesyl (C15) and ... more Modification of proteins at C-terminal cysteine residue(s) by the isoprenoids farnesyl (C15) and geranylgeranyl (C20) is essential for the biological function of a number of eukaryotic proteins including fungal mating factors and the small, GTP-binding proteins of the Ras superfamily. Three distinct enzymes, conserved between yeast and mammals, have been identified that prenylate proteins: farnesyl protein transferase, geranylgeranyl protein transferase type I and geranylgeranyl protein transferase type II. Each prenyl protein transferase has its own protein substrate specificity. Much has been learned about the biology, genetics and biochemistry of protein prenylation and prenyl protein transferases through studies of eukaryotic microorganisms, particularly Saccharomyces cerevisiae. The functional importance of protein prenylation was first demonstrated with fungal mating factors. The initial genetic analysis of prenyl protein transferases was in S. cerevisiae with the isolation and subsequent characterization of mutations in the RAM1, RAM2, CDC43 and BET2 genes, each of which encodes a prenyl protein transferase subunit. We review here these and other studies on protein prenylation in eukaryotic microbes and how they relate to and have contributed to our knowledge about protein prenylation in all eukaryotic cells.
Journal of Medicinal Chemistry, 2007
A new series of MEK1 inhibitors, the 4-anilino-5-carboxamido-2-pyridones, were designed and synth... more A new series of MEK1 inhibitors, the 4-anilino-5-carboxamido-2-pyridones, were designed and synthesized using a combination of medicinal chemistry, computational chemistry, and structural elucidation. The effect of variation in the carboxamide side chain, substitution on the pyridone nitrogen, and replacement of the 4'-iodide were all investigated. This study afforded several compounds which were either equipotent or more potent than the clinical candidate CI-1040 (1) in an isolated enzyme assay, as well as murine colon carcinoma (C26) cells, as measured by suppression of phosphorylated ERK substrate. Most notably, pyridone 27 was found to be more potent than 1 in vitro and produced a 100% response rate at a lower dose than 1, when tested for in vivo efficacy in animals bearing C26 tumors.
Journal of Medicinal Chemistry, 2001
The synthesis, structure-activity relationships, and biological properties of a novel series of i... more 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.
Journal of Biological Chemistry, 1997
The roles of 11 conserved amino acids of the beta-subunit of human farnesyl:protein transferase (... more The roles of 11 conserved amino acids of the beta-subunit of human farnesyl:protein transferase (FTase) were examined by performing kinetic and biochemical analyses of site-directed mutants. This biochemical information along with the x-ray crystal structure of rat FTase indicates that residues His-248, Arg-291, Lys-294, and Trp-303 are involved with binding and utilization of the substrate farnesyl diphosphate. Our data confirm structural evidence that amino acids Cys-299, Asp-297, and His-362 are ligands for the essential Zn2+ ion and suggest that Asp-359 may also play a role in Zn2+ binding. Additionally, we demonstrate that Arg-202 is important for binding the essential C-terminal carboxylate of the protein substrate.
Current Opinion in Chemical Biology, 1997
Over the past few years, the idea that farnesyl-protein transferase (FPTase) inhibitors might be ... more Over the past few years, the idea that farnesyl-protein transferase (FPTase) inhibitors might be effective antiproliferativelantitumor agents has been realized in studies of cultured cells and in rodent models of cancer. Most of the studies with FPTase inhibitors have focused on inhibiting the growth of ras-transformed cells in vitro or the growth of ras-dependent tumors in mice. More recently, it has been recognized that the antiproliferative effect of FPTase inhibitors may extend beyond ras-driven tumors. It now seems likely that the ability of FPTase inhibitors to reverse the malignant phenotype results, at least in part, from inhibiting the farnesylation of proteins other than Ras. Addresses Boyartchuk VL, Ashby MN, Rine J: Modulation of Ras and afactor function by carboxyl-terminal proteolysis. Science 1997, 275:1796-l 600. First molecular characterization of a CaaX protease. Genetic inhibition of the protease inhibited Ras function in yeast but was not toxic to the yeast. This work should lead to the cloning of mammalian CaaX protease, which is a potential target for the development of inhibitors with anti-Ras activity. 9. Clarke S: Protein isoprenylation and methylation at carboxylterminal cysteine residues. Annu Rev Biochem 1992, 61:355-386. 10. Dudler T, Gelb MH: Palmitoylation of Ha-Ras facilitates membrane binding, activation of downstream effecters. and meiotic maturation in Xenopus oocytes. J Biol Chem 1996, 271 :11541-l 1547. Farnesyltransferase inhibitors versus Ras inhibitors Gibbs et a/. 203 22. James GL, Goldstein JL, Brown MS: Polylysine and CVIM sequences of K-RasB dictate specificity of prenylation and confer resistance to benzodiazepine peptidomimetic in vitro. J Biol Chem 1995, 270:6221-6226. 23. Rowell CA, Kowalczyk JJ, Lewis MD, Garcia AM: Direct . . demonstration of geranylgeranylation and farnesylation of Ki-Ras in Go. J Biol Chem 1997, 272:14093-l 4097. Please see annotation I1 5.01.
Breast Cancer Research and Treatment, 1996
The oncoprotein encoded by mutant ras genes is initially synthesized as a cytoplasmic precursor w... more The oncoprotein encoded by mutant ras genes is initially synthesized as a cytoplasmic precursor which requires posttranslational processing to attain biological activity; farnesylation of the cysteine residue present in the CaaX motif located at the carboxy-terminus of all Ras proteins is ...
Bioorganic & Medicinal Chemistry Letters, 2011
Bioorganic & Medicinal Chemistry Letters, 2009
3-Amido-4-anilinoquinolines are potent and highly selective inhibitors of CSF-1R. Their synthesis... more 3-Amido-4-anilinoquinolines are potent and highly selective inhibitors of CSF-1R. Their synthesis and SAR is reported, along with initial efforts to optimize the physical properties and PK through modifications at the quinoline 6-and 7-positions.
Bioorganic & Medicinal Chemistry Letters, 2009
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / b m c l in our ce... more j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / b m c l in our cell assay (4.2 lM). The 2,3-Cl example 11 was closer to the level of potency we felt was required (0.44 lM in the cell), but still significantly less active than the corresponding 7-MeO compound 5.
Bioorganic & Medicinal Chemistry Letters, 2013
The potent and selective 3-amido-4-anilinoquinoline CSF-1R inhibitor AZ683 suffered from cardiova... more The potent and selective 3-amido-4-anilinoquinoline CSF-1R inhibitor AZ683 suffered from cardiovascular liabilities, which were linked to the off-target activities of the compound and ion channel activity in particular. Less basic and less lipophilic examples from both the quinoline and cinnoline series demonstrated cleaner secondary pharmacology profiles. Cinnoline 31 retained the required potency and oral PK profile, and was progressed through the safety screening cascade to be nominated into development as AZD7507.