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8 results on '"Aaron Coffin"'

1. Modulation of macrophage inflammatory function through selective inhibition of the epigenetic reader protein SP140

Author

Mohammed Ghiboub, Jan Koster, Peter D. Craggs, Andrew Y. F. Li Yim, Anthony Shillings, Sue Hutchinson, Ryan P. Bingham, Kelly Gatfield, Ishtu L. Hageman, Gang Yao, Heather P. O’Keefe, Aaron Coffin, Amish Patel, Lisa A. Sloan, Darren J. Mitchell, Thomas G. Hayhow, Laurent Lunven, Robert J. Watson, Christopher E. Blunt, Lee A. Harrison, Gordon Bruton, Umesh Kumar, Natalie Hamer, John R. Spaull, Danny A. Zwijnenburg, Olaf Welting, Theodorus B. M. Hakvoort, Anje A. te Velde, Johan van Limbergen, Peter Henneman, Rab K. Prinjha, Menno P. J. de Winther, Nicola R. Harker, David F. Tough, and Wouter J. de Jonge

Subjects
Macrophage, Crohn's disease, SP140, Biology (General), QH301-705.5
Abstract

Abstract Background SP140 is a bromodomain-containing protein expressed predominantly in immune cells. Genetic polymorphisms and epigenetic modifications in the SP140 locus have been linked to Crohn’s disease (CD), suggesting a role in inflammation. Results We report the development of the first small molecule SP140 inhibitor (GSK761) and utilize this to elucidate SP140 function in macrophages. We show that SP140 is highly expressed in CD mucosal macrophages and in in vitro-generated inflammatory macrophages. SP140 inhibition through GSK761 reduced monocyte-to-inflammatory macrophage differentiation and lipopolysaccharide (LPS)-induced inflammatory activation, while inducing the generation of CD206+ regulatory macrophages that were shown to associate with a therapeutic response to anti-TNF in CD patients. SP140 preferentially occupies transcriptional start sites in inflammatory macrophages, with enrichment at gene loci encoding pro-inflammatory cytokines/chemokines and inflammatory pathways. GSK761 specifically reduces SP140 chromatin binding and thereby expression of SP140-regulated genes. GSK761 inhibits the expression of cytokines, including TNF, by CD14+ macrophages isolated from CD intestinal mucosa. Conclusions This study identifies SP140 as a druggable epigenetic therapeutic target for CD.

Published
2022
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2. Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening

Author

Carl A. Machutta, Christopher S. Kollmann, Kenneth E. Lind, Xiaopeng Bai, Pan F. Chan, Jianzhong Huang, Lluis Ballell, Svetlana Belyanskaya, Gurdyal S. Besra, David Barros-Aguirre, Robert H. Bates, Paolo A. Centrella, Sandy S. Chang, Jing Chai, Anthony E. Choudhry, Aaron Coffin, Christopher P. Davie, Hongfeng Deng, Jianghe Deng, Yun Ding, Jason W. Dodson, David T. Fosbenner, Enoch N. Gao, Taylor L. Graham, Todd L. Graybill, Karen Ingraham, Walter P. Johnson, Bryan W. King, Christopher R. Kwiatkowski, Joël Lelièvre, Yue Li, Xiaorong Liu, Quinn Lu, Ruth Lehr, Alfonso Mendoza-Losana, John Martin, Lynn McCloskey, Patti McCormick, Heather P. O’Keefe, Thomas O’Keeffe, Christina Pao, Christopher B. Phelps, Hongwei Qi, Keith Rafferty, Genaro S. Scavello, Matt S. Steiginga, Flora S. Sundersingh, Sharon M. Sweitzer, Lawrence M. Szewczuk, Amy Taylor, May Fern Toh, Juan Wang, Minghui Wang, Devan J. Wilkins, Bing Xia, Gang Yao, Jean Zhang, Jingye Zhou, Christine P. Donahue, Jeffrey A. Messer, David Holmes, Christopher C. Arico-Muendel, Andrew J. Pope, Jeffrey W. Gross, and Ghotas Evindar

Subjects
Science
Abstract

Encoded Library Technology (ELT) has streamlined the identification of chemical ligands for protein targets in drug discovery. Here, the authors optimize the ELT approach to screen multiple proteins in parallel and identify promising targets and antibacterial compounds forS. aureus, A. baumannii and M. tuberculosis.

Published
2017
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3. Correction: Author Correction: Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening

Author

Carl A. Machutta, Christopher S. Kollmann, Kenneth E. Lind, Xiaopeng Bai, Pan F. Chan, Jianzhong Huang, Lluis Ballell, Svetlana Belyanskaya, Gurdyal S. Besra, David Barros-Aguirre, Robert H. Bates, Paolo A. Centrella, Sandy S. Chang, Jing Chai, Anthony E. Choudhry, Aaron Coffin, Christopher P. Davie, Hongfeng Deng, Jianghe Deng, Yun Ding, Jason W. Dodson, David T. Fosbenner, Enoch N. Gao, Taylor L. Graham, Todd L. Graybill, Karen Ingraham, Walter P. Johnson, Bryan W. King, Christopher R. Kwiatkowski, Joël Lelièvre, Yue Li, Xiaorong Liu, Quinn Lu, Ruth Lehr, Alfonso Mendoza-Losana, John Martin, Lynn McCloskey, Patti McCormick, Heather P. O’Keefe, Thomas O’Keeffe, Christina Pao, Christopher B. Phelps, Hongwei Qi, Keith Rafferty, Genaro S. Scavello, Matt S. Steiginga, Flora S. Sundersingh, Sharon M. Sweitzer, Lawrence M. Szewczuk, Amy Taylor, May Fern Toh, Juan Wang, Minghui Wang, Devan J. Wilkins, Bing Xia, Gang Yao, Jean Zhang, Jingye Zhou, Christine P. Donahue, Jeffrey A. Messer, David Holmes, Christopher C. Arico-Muendel, Andrew J. Pope, Jeffrey W. Gross, and Ghotas Evindar

Subjects
Science
Abstract

Nature Communications 8: Article number: 16081 (2017); Published: 17 July 2017, Updated: 13 July 2018 The original version of this Article omitted the following from the Acknowledgements: ‘We thank Robert Kirkpatrick for implementing the high throughput protein design strategy that enabled screeningand triage of essential A.

Published
2018
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5. Selective Synthesis of (+)-Dysoline

Author

Aaron Coffin and Joseph M. Ready

Subjects
010405 organic chemistry, Chemistry, Stereochemistry, Organic Chemistry, Enantioselective synthesis, Regioselectivity, 010402 general chemistry, Ring (chemistry), 01 natural sciences, Biochemistry, 0104 chemical sciences, chemistry.chemical_compound, Danheiser benzannulation, Aldol reaction, Chromone, HT1080, Piperidine, Physical and Theoretical Chemistry
Abstract

Dysoline, a novel chromone alkaloid isolated from Dysoxylum binectariferum, was reported to have selective cytotoxicity for HT1080 fibrosarcoma cells (IC50 of 0.21 μM). Given the scarcity of natural material, a concise synthesis of (+)-dysoline was developed, allowing for further biological evaluation. An enantioselective nucleophile-catalyzed aldol lactonization formed the piperidine ring with control of relative and absolute stereochemistry. Construction of the C6-chromone core with complete regioselectivity was achieved using a Danheiser benzannulation.

Published
2019

6. Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening

Author

Todd L. Graybill, John D. Martin, Jason W. Dodson, Hongfeng Deng, Christopher P. Davie, Christopher C. Arico-Muendel, Minghui Wang, Hongwei Qi, Sandy S. Chang, David J. Holmes, Karen A. Ingraham, Kenneth E Lind, Heather O’Keefe, Carl A. Machutta, David Barros-Aguirre, Christine Patricia Donahue, Christina S. Pao, Jeffrey W. Gross, Ghotas Evindar, Jean Zhang, Bing Xia, Juan Wang, Patti McCormick, Xiaorong Liu, Jianzhong Huang, Joël Lelièvre, Quinn Lu, Pan F. Chan, Matt S. Steiginga, Lynn McCloskey, Christopher S. Kollmann, Taylor L. Graham, Xiaopeng Bai, Jing Chai, Yue Li, Walter P. Johnson, Ruth Lehr, Lawrence M. Szewczuk, Jingye Zhou, Lluis Ballell, Genaro S. Scavello, Robert H. Bates, Anthony E. Choudhry, Aaron Coffin, Sharon Sweitzer, Christopher R. Kwiatkowski, Andrew J. Pope, Enoch Gao, Christopher B. Phelps, David T. Fosbenner, Keith Rafferty, Thomas O’Keeffe, Gang Yao, Bryan W. King, Svetlana L. Belyanskaya, May Fern Toh, Gurdyal S. Besra, Amy N. Taylor, Devan J. Wilkins, Alfonso Mendoza-Losana, Paolo A. Centrella, Flora S. Sundersingh, Jeffrey A. Messer, Yun Ding, and Jianghe Deng

Subjects
0301 basic medicine, Acinetobacter baumannii, Staphylococcus aureus, Computer science, Science, Drug Evaluation, Preclinical, General Physics and Astronomy, Computational biology, Bioinformatics, Article, General Biochemistry, Genetics and Molecular Biology, Small Molecule Libraries, 03 medical and health sciences, chemistry.chemical_compound, Drug Discovery, Molecular Targeted Therapy, Gene Library, Multidisciplinary, Drug discovery, Correction, General Chemistry, Mycobacterium tuberculosis, Anti-Bacterial Agents, 030104 developmental biology, chemistry, Identification (biology), DNA
Abstract

The identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins. This concept was further explored by screening 42 targets from Mycobacterium tuberculosis. Active chemical series for six targets from our initial effort as well as three chemotypes for DHFR from M. tuberculosis are reported. The findings demonstrate that parallel ELT selections can be used to assess ligandability and highlight opportunities for successful lead and tool discovery., Encoded Library Technology (ELT) has streamlined the identification of chemical ligands for protein targets in drug discovery. Here, the authors optimize the ELT approach to screen multiple proteins in parallel and identify promising targets and antibacterial compounds for S. aureus, A. baumannii and M. tuberculosis.

Published
2016

7. 5-Aryl-4-carboxamide-1,3-oxazoles: potent and selective GSK-3 inhibitors

Author

Angela Bridges, Gang Yao, Geoffrey J. Cutler, Paul Bamborough, Svetlana L. Belyanskaya, Caroline Brough, Gabriella Gentile, Benjamin D. Bax, Margarete Neu, Aaron Coffin, Giancarlo Merlo, Paul S. Carter, Giovanni Bernasconi, and Alfonso Pozzan

Subjects
Models, Molecular, Bipolar Disorder, medicine.drug_class, Clinical Biochemistry, Pharmaceutical Science, Carboxamide, Biochemistry, Cell activity, chemistry.chemical_compound, Glycogen Synthase Kinase 3, Structure-Activity Relationship, GSK-3, Drug Discovery, medicine, Animals, Humans, Molecular Biology, Oxazoles, Protein Kinase Inhibitors, Chemistry, Aryl, Organic Chemistry, Brain, Combinatorial chemistry, Rats, Molecular Medicine
Abstract

5-Aryl-4-carboxamide-1,3-oxazoles are a novel, potent and selective series of GSK-3 inhibitors. The optimization of the series to yield compounds with cell activity and brain permeability is described.

Published
2011

8. Efforts at Expanding the Scope of Peptides as Enantioselective Organic Catalysts

Author

Coffin, Aaron (Coffin, Aaron)

Subjects
organic catalyst, organic synthesis, kinetic resolutions, enantioselective catalysis, peptide catalyst
Abstract

The development of peptides as catalysts for preparing optically active molecules is an ongoing investigation. Efforts at expanding the use of peptides are explored in two ways: investigating novel reactions in which peptides can act as asymmetric catalysts and through expanding the substrate scope of peptides in performing kinetic resolutions. Attempts at furthering the reaction scope of acylsulfonamide-containing peptides to act as BrØnsted acids through promoting the attack of 7-methyl oct-6-ene-1-tosylaziridine (9) by an internal π-nucleophile are discussed herein. Also reported is the use of pentameric peptides containing a π(-methyl)histidine residue in the kinetic resolution of the primary alcohol 4-hydroxymethyl cyclopent-2-enone (76) and the secondary aliphatic alcohol 2- pentanol. Moderate selectivities were observed in the kinetic resolution of 4-hydroxymethyl cyclopent-2-enone (76) and promising results were obtained in the initial screening of catalysts for the resolution of 2-pentanol.

Published
2008

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