14 results on '"Camilo E. Quevedo"'
Search Results
2. Correction: BRET-based RAS biosensors that show a novel small molecule is an inhibitor of RAS-effector protein-protein interactions
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Nicolas Bery, Abimael Cruz-Migoni, Carole JR Bataille, Camilo E Quevedo, Hanna Tulmin, Ami Miller, Angela Russell, Simon EV Phillips, Stephen B Carr, and Terence H Rabbitts
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Medicine ,Science ,Biology (General) ,QH301-705.5 - Published
- 2018
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3. BRET-based RAS biosensors that show a novel small molecule is an inhibitor of RAS-effector protein-protein interactions
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Nicolas Bery, Abimael Cruz-Migoni, Carole JR Bataille, Camilo E Quevedo, Hanna Tulmin, Ami Miller, Angela Russell, Simon EV Phillips, Stephen B Carr, and Terence H Rabbitts
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RAS ,BRET ,biosensors ,protein-protein interaction inhibition ,cell-based assays ,intracellular antibody ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
The RAS family of proteins is amongst the most highly mutated in human cancers and has so far eluded drug therapy. Currently, much effort is being made to discover mutant RAS inhibitors and in vitro screening for RAS-binding drugs must be followed by cell-based assays. Here, we have developed a robust set of bioluminescence resonance energy transfer (BRET)-based RAS biosensors that enable monitoring of RAS-effector interaction inhibition in living cells. These include KRAS, HRAS and NRAS and a variety of different mutations that mirror those found in human cancers with the major RAS effectors such as CRAF, PI3K and RALGDS. We highlighted the utility of these RAS biosensors by showing a RAS-binding compound is a potent pan-RAS-effector interactions inhibitor in cells. The RAS biosensors represent a useful tool to investigate and characterize the potency of anti-RAS inhibitors in cells and more generally any RAS protein-protein interaction (PPI) in cells.
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- 2018
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4. A novel color change mechanism for breast cancer biomarker detection: naphthoquinones as specific ligands of human arylamine N-acetyltransferase 1.
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Nicola Laurieri, James E Egleton, Amy Varney, Cyrille C Thinnes, Camilo E Quevedo, Peter T Seden, Sam Thompson, Fernando Rodrigues-Lima, Julien Dairou, Jean-Marie Dupret, Angela J Russell, and Edith Sim
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Medicine ,Science - Abstract
Human arylamine N-acetyltransferase 1 (hNAT1) has become an attractive potential biomarker for estrogen-receptor-positive breast cancers. We describe here the mechanism of action of a selective non-covalent colorimetric biosensor for the recognition of hNAT1 and its murine homologue, mNat2, over their respective isoenzymes, leading to new opportunities in diagnosis. On interaction with the enzyme, the naphthoquinone probe undergoes an instantaneous and striking visible color change from red to blue. Spectroscopic, chemical, molecular modelling and biochemical studies reported here show that the color change is mediated by selective recognition between the conjugate base of the sulfonamide group within the probe and the conjugate acid of the arginine residue within the active site of both hNAT1 and mNat2. This represents a new mechanism for selective biomarker sensing and may be exploited as a general approach to the specific detection of biomarkers in disease.
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- 2013
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5. Abstract LB-068: From intracellular antibody fragments to small molecule inhibitors of mutant KRAS
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Simon E. V. Phillips, Carole J. R. Bataille, Tomoyuki Tanaka, Angela J. Russell, Abimael Cruz, Terence H. Rabbitts, Donna Petch, Hanna Tulmin, and Camilo E. Quevedo
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Cancer Research ,Oncology ,Chemistry ,Mutant ,medicine ,KRAS ,medicine.disease_cause ,Molecular biology ,Small molecule ,Intracellular ,Antibody fragments - Abstract
Our aim was to develop methods to employ intracellular antibody fragments as lead macromolecules for small compound selections. We have used this approach to identify small molecules binding to mutant RAS with potential to inhibit the RAS-effector interactions. Mutation in RAS family members is among the most frequent in human cancer and the mutant RAS proteins are tumour-specific proteins for therapy. We have previously selected an intracellular antibody single domain fragment that binds to mutant forms of KRAS and HRAS and used this antibody fragment to demonstrate that blocking RAS-effector interaction-dependent signal transduction prevents tumour initiation and overt tumour growth in mouse preclinical models. The antibody fragment binds to GTP-bound RAS with high pM affinity and we have used this property to isolate compounds from a fragment library using a competitive SPR method that places the compounds in the region of the binding site of the antibody fragment. Using a combination of X-ray crystallography and medicinal chemistry, we have obtained a family of compounds that bind adjacent to the KRAS switch I region with nM affinity and that inhibit the downstream phosphorylation of AKT and ERK that results from RAS signaling. The chemical evolution and interaction characteristics of the KRAS-binding compounds will be described and their biochemical and cell-based properties presented. We have validated our approach using an antibody fragment as a screening tool for the identification of small molecule inhibitors of the RAS-effector interaction. This approach has yielded small compound fragments that are currently being developed as potential RAS-effector inhibitors in our medicinal chemistry programme. Citation Format: Camilo E. Quevedo, Abimael Cruz, Hanna Tulmin, Carole J. Bataille, Tomoyuki Tanaka, Donna Petch, Angela J. Russell, Simon Phillips, Terence H. Rabbitts. From intracellular antibody fragments to small molecule inhibitors of mutant KRAS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-068. doi:10.1158/1538-7445.AM2017-LB-068
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- 2019
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6. Aminothiazolones as potent, selective and cell active inhibitors of the PIM kinase family
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Carole J. R. Bataille, Alan M. Jones, Simon Byrne, Abigail R R Guillermo, Graham Michael Wynne, Angela J. Russell, J.M. Elkins, Isabel V.L. Wilkinson, Stefan Knapp, Camilo E. Quevedo, Matthew J. Durbin, Roderick G. Walker, Stephen G. Davies, and Anna Nadali
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Models, Molecular ,Clinical Biochemistry ,Pharmaceutical Science ,PIM1 ,01 natural sciences ,Biochemistry ,Serine ,Structure-Activity Relationship ,Proto-Oncogene Proteins c-pim-1 ,hemic and lymphatic diseases ,Drug Discovery ,Humans ,Structure–activity relationship ,Protein Kinase Inhibitors ,Molecular Biology ,ADME ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Kinase ,Chemistry ,Organic Chemistry ,0104 chemical sciences ,Thiazoles ,010404 medicinal & biomolecular chemistry ,Molecular Medicine ,Phosphorylation ,Efflux ,Intracellular - Abstract
We have previously reported the discovery of a series of rhodanine-based inhibitors of the PIM family of serine/threonine kinases. Here we described the optimisation of those compounds to improve their physicochemical and ADME properties as well as reducing their off-targets activities against other kinases. Through molecular modeling and systematic structure activity relationship (SAR) studies, advanced molecules with high inhibitory potency, reduced off-target activity and minimal efflux were identified as new pan-PIM inhibitors. One example of an early lead, OX01401, was found to inhibit PIMs with nanomolar potency (15 nM for PIM1), inhibit proliferation of two PIM-expressing leukaemic cancer cell lines, MV4-11 and K562, and to reduce intracellular phosphorylation of a PIM substrate in a concentration dependent manner.
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- 2020
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7. Author response: BRET-based RAS biosensors that show a novel small molecule is an inhibitor of RAS-effector protein-protein interactions
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Nicolas Bery, Abimael Cruz-Migoni, Carole JR Bataille, Camilo E Quevedo, Hanna Tulmin, Ami Miller, Angela Russell, Simon EV Phillips, Stephen B Carr, and Terence H Rabbitts
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- 2018
- Full Text
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8. Intracellular immunization against HIV infection with an intracellular antibody that mimics HIV integrase binding to the cellular LEDGF protein
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Wilawan Bunjobpol, Denis Ptchelkine, Abimael Cruz-Mignoni, Simon E. V. Phillips, Camilo E. Quevedo, Terence H. Rabbitts, Jennifer S. Chambers, Mariliza Derveni, Alison Simmons, Mei-Yi Sun, Clare Hannon, Ami Miller, and Leyuan Bao
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0301 basic medicine ,CD4-Positive T-Lymphocytes ,T cell ,HIV Core Protein p24 ,lcsh:Medicine ,HIV Infections ,HIV Integrase ,Molecular Dynamics Simulation ,Crystallography, X-Ray ,Virus Replication ,Jurkat cells ,Virus ,Article ,03 medical and health sciences ,Jurkat Cells ,Mice ,Two-Hybrid System Techniques ,medicine ,Animals ,Humans ,Amino Acid Sequence ,lcsh:Science ,Multidisciplinary ,Binding Sites ,biology ,Chromatin binding ,lcsh:R ,Single-Domain Antibodies ,Virology ,3. Good health ,Integrase ,030104 developmental biology ,medicine.anatomical_structure ,Single-domain antibody ,Viral replication ,biology.protein ,Intercellular Signaling Peptides and Proteins ,lcsh:Q ,Antibody ,Sequence Alignment ,Protein Binding - Abstract
Preventing the protein-protein interaction of the cellular chromatin binding protein Lens Epithelium-Derived Growth Factor (LEDGF) and human immunodeficiency virus (HIV) integrase is an important possible strategy for anti-viral treatment for AIDS. We have used Intracellular Antibody Capture technology to isolate a single VH antibody domain that binds to LEDGF. The crystal structure of the LEDGF-VH complex reveals that the single domain antibody mimics the effect of binding of HIV integrase to LEDGF which is crucial for HIV propagation. CD4-expressing T cell lines were constructed to constitutively express the LEDGF-binding VH and these cells showed interference with HIV viral replication, assayed by virus capsid protein p24 production. Therefore, pre-conditioning cells to express antibody fragments confers effective intracellular immunization for preventing chronic viral replication and can be a way to prevent HIV spread in infected patients. This raises the prospect that intracellular immunization strategies that focus on cellular components of viral integrase protein interactions can be used to combat the problems associated with latent HIV virus re-emergence in patients. New genome editing development, such as using CRISPR/cas9, offer the prospect intracellularly immunized T cells in HIV+ patients.
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- 2017
9. Thiazolidine derivatives as potent and selective inhibitors of the PIM kinase family
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Carole J. R. Bataille, Matthew J. Durbin, Angela J. Russell, Anna Nadali, Méabh B. Brennan, Robert Westwood, Stefan Knapp, Oleg Fedorov, Roderick G. Walker, Kilian Huber, Graham Michael Wynne, Stephen G. Davies, Alan M. Jones, Gu Liu, Camilo E. Quevedo, and Simon Byrne
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0301 basic medicine ,Molecular model ,Rhodanine ,Clinical Biochemistry ,Thiazolidine ,Pharmaceutical Science ,Antineoplastic Agents ,Protein Serine-Threonine Kinases ,Biochemistry ,Serine ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Proto-Oncogene Proteins c-pim-1 ,hemic and lymphatic diseases ,Proto-Oncogene Proteins ,Drug Discovery ,Animals ,Humans ,Threonine ,Molecular Biology ,IC50 ,Protein Kinase Inhibitors ,Sulfonamides ,Chemistry ,Kinase ,Organic Chemistry ,In vitro ,3. Good health ,Isoenzymes ,Molecular Docking Simulation ,030104 developmental biology ,Drug development ,Solubility ,Microsomes, Liver ,Molecular Medicine ,Thiazolidines ,K562 Cells - Abstract
The PIM family of serine/threonine kinases have become an attractive target for anti-cancer drug development, particularly for certain hematological malignancies. Here, we describe the discovery of a series of inhibitors of the PIM kinase family using a high throughput screening strategy. Through a combination of molecular modeling and optimization studies, the intrinsic potencies and molecular properties of this series of compounds was significantly improved. An excellent pan-PIM isoform inhibition profile was observed across the series, while optimized examples show good selectivity over other kinases. Two PIM-expressing leukemic cancer cell lines, MV4-11 and K562, were employed to evaluate the in vitro anti-proliferative effects of selected inhibitors. Encouraging activities were observed for many examples, with the best example (44) giving an IC50 of 0.75μM against the K562 cell line. These data provide a promising starting point for further development of this series as a new cancer therapy through PIM kinase inhibition.
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- 2017
10. Thermal Elimination of Diethyldithiocarbamates and Application in the Synthesis of (±)-Ferrugine
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Paolo Innocenti, Camilo E. Quevedo, Luke A. Baker, Richard S. Grainger, and Shamim Ahmed
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chemistry.chemical_classification ,Lactams ,Bicyclic molecule ,Organic Chemistry ,Diphenyl ether ,Temperature ,Stereoisomerism ,Bridged Bicyclo Compounds, Heterocyclic ,Medicinal chemistry ,Chemical synthesis ,chemistry.chemical_compound ,chemistry ,Cyclization ,Amide ,Lactam ,Organic chemistry ,Ditiocarb ,Dithiocarbamate ,Phenyllithium ,Octane - Abstract
Dithiocarbamate-substituted lactams, prepared through group-transfer cyclization reactions of carbamoyl radicals, undergo a Chugaev-like thermal elimination of the dithiocarbamate group in refluxing diphenyl ether to form alpha,beta- and/or beta,gamma-unsaturated amides, depending on the structure of the starting material. This reaction sequence was used to prepare an unsaturated [3.2.2] bridged bicyclic amide, which was converted in a one-pot procedure to the 8-azabicyclo[3.2.1]octane ring system of the tropane alkaloid ferrugine by treatment with phenyllithium followed by aqueous sodium hydroxide.
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- 2008
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11. Microwave-assisted synthesis of 2-aminonicotinic acids by reacting 2-chloronicotinic acid with amines
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Camilo E. Quevedo, Edward McDonald, and Vassilios Bavetsias
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Solvent ,Reaction conditions ,Chemistry ,Microwave heating ,Yield (chemistry) ,Organic Chemistry ,Drug Discovery ,Microwave irradiation ,Organic chemistry ,Amine gas treating ,Biochemistry ,Medicinal chemistry ,Microwave assisted - Abstract
2-(Methylamino)nicotinic acid was readily prepared in high yield by reacting 2-chloronicotinic acid with 40% aq MeNH2 under microwave irradiation either at 120 degrees for 2 h or at 140 degrees C for 1.5 h. Subsequently, we found that a range of 2-aminonicotinic acids could be obtained under microwave heating. The optimal reaction conditions involved the use of 3 equiv of amine, water as the solvent and heating at 200 degrees C for 2 h in the presence of diisopropylethylamine (3 equiv). (C) 2009 Elsevier Ltd. All rights reserved.
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- 2009
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12. A Useful Approach To Identify Novel Small Molecule Inhibitors Of Wnt-Dependent Transcription
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Branko V. Latinkić, Camilo E. Quevedo, Julian Blagg, Bożena Pajak, Lee Samuel, Helen Todd, Alysia Battersby, Ruth Ruddle, Wynne Aherne, Kenneth Burnside Ramsay Ewan, Mark Stubbs, Paul Workman, Florence I. Raynaud, Edward McDonald, Olivier Barbeau, Hannah Botfield, Nicholas D. Allen, Rodrigo M. Young, Trevor Clive Dale, and Stephen W. Wilson
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Cancer Research ,Cell signaling ,Transcription, Genetic ,Antineoplastic Agents ,Article ,Chemical library ,chemistry.chemical_compound ,Mice ,Xenopus laevis ,L Cells ,GSK-3 ,Cell Line, Tumor ,Animals ,Humans ,Zebrafish ,Transcription factor ,biology ,Wnt signaling pathway ,biology.organism_classification ,Cell biology ,High-Throughput Screening Assays ,Wnt Proteins ,Oncology ,chemistry ,Phosphorylation ,Signal transduction ,Drug Screening Assays, Antitumor ,Signal Transduction - Abstract
The Wnt signaling pathway is frequently deregulated in cancer due to mutations in genes encoding APC, β-catenin, and axin. To identify small-molecule inhibitors of Wnt signaling as potential therapeutics, a diverse chemical library was screened using a transcription factor reporter cell line in which the activity of the pathway was induced at the level of Disheveled protein. A series of deconvolution studies was used to focus on three compound series that selectively killed cancer cell lines with constitutive Wnt signaling. Activities of the compounds included the ability to induce degradation of β-catenin that had been stabilized by a glycogen synthase kinase-3 (GSK-3) inhibitor. This screen illustrates a practical approach to identify small-molecule inhibitors of Wnt signaling that can seed the development of agents suitable to treat patients with Wnt-dependent tumors. Cancer Res; 70(14); 5963–73. ©2010 AACR.
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- 2010
13. ChemInform Abstract: Microwave-Assisted Synthesis of 2-Aminonicotinic Acids by Reacting 2-Chloronicotinic Acid with Amines
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Edward McDonald, Vassilios Bavetsias, and Camilo E. Quevedo
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Reaction conditions ,Solvent ,Chemistry ,Microwave heating ,Yield (chemistry) ,Microwave irradiation ,Amine gas treating ,General Medicine ,Medicinal chemistry ,Microwave assisted - Abstract
2-(Methylamino)nicotinic acid was readily prepared in high yield by reacting 2-chloronicotinic acid with 40% aq MeNH2 under microwave irradiation either at 120 degrees for 2 h or at 140 degrees C for 1.5 h. Subsequently, we found that a range of 2-aminonicotinic acids could be obtained under microwave heating. The optimal reaction conditions involved the use of 3 equiv of amine, water as the solvent and heating at 200 degrees C for 2 h in the presence of diisopropylethylamine (3 equiv). (C) 2009 Elsevier Ltd. All rights reserved.
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- 2009
- Full Text
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14. ChemInform Abstract: Thermal Elimination of Diethyldithiocarbamates and Application in the Synthesis of (.+-.)-Ferrugine
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Luke A. Baker, Richard S. Grainger, Shamim Ahmed, Camilo E. Quevedo, and Paolo Innocenti
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chemistry.chemical_classification ,chemistry.chemical_compound ,Elimination reaction ,Bicyclic molecule ,Chemistry ,Amide ,Diphenyl ether ,General Medicine ,Dithiocarbamate ,Medicinal chemistry ,Tropane alkaloid ,Phenyllithium ,Octane - Abstract
Dithiocarbamate-substituted lactams, prepared through group-transfer cyclization reactions of carbamoyl radicals, undergo a Chugaev-like thermal elimination of the dithiocarbamate group in refluxing diphenyl ether to form alpha,beta- and/or beta,gamma-unsaturated amides, depending on the structure of the starting material. This reaction sequence was used to prepare an unsaturated [3.2.2] bridged bicyclic amide, which was converted in a one-pot procedure to the 8-azabicyclo[3.2.1]octane ring system of the tropane alkaloid ferrugine by treatment with phenyllithium followed by aqueous sodium hydroxide.
- Published
- 2009
- Full Text
- View/download PDF
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