I03-Macromolecular Crystallography
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Christopher P.
Tinworth
,
Justyna
Wojno-Picon
,
Michael
Adam
,
Stephan
Gade
,
Ashley P.
Hancock
,
David J.
Hirst
,
Jonathan P.
Hutchinson
,
Semra
Kitchen
,
Despoina
Koumantou
,
Jonathan
Lea
,
Stephanie
Lehmann
,
John
Liddle
,
Richard
Lonsdale
,
Margarete
Neu
,
Leng
Nickels
,
Alex
Phillipou
,
James E.
Rowedder
,
Paul
Rowland
,
Jessica L.
Schneck
,
Paul
Scott-Stevens
,
Hester
Sheehan
,
Michael
Steidel
,
Chloe L.
Tayler
,
Ioannis
Temponeras
,
Kevin
Thang
,
David F.
Tough
,
Giovanni
Vitulli
,
Ian D.
Wall
,
Robert J.
Young
,
Nico
Zinn
,
Simon
Peace
,
Efstratios
Stratikos
Diamond Proposal Number(s):
[37907]
Abstract: Endoplasmic reticulum aminopeptidase 1 (ERAP1) regulates immune responses by proteolytically processing peptides presented by major histocompatibility class I molecules (MHC-I). ERAP1 can reduce the immunogenicity of cancer cells by destroying cancer-associated antigenic peptides or contribute to autoimmunity by generating self-antigenic peptides. ERAP1 inhibition has emerged as a tractable approach for cancer immunotherapy and specific classes of autoimmune diseases. We describe the discovery of a potent and selective ERAP1 inhibitor that targets its regulatory allosteric site. The compound has favorable in vivo pharmacokinetics, oral bioavailability, can regulate the immunopeptidome of cancer cells, and enhance tumor antigenicity in vivo controlling growth. When administered in the murine collagen-induced arthritis model, we observed no exacerbation of autoimmune responses but rather a dose-dependent therapeutic benefit. Our results demonstrate that ERAP1 inhibition is a tractable approach to modulating immune responses, provide mechanistic insight, and are valuable in vivo tools for interrogating ERAP1 biology and further drug development.
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Jun 2026
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I03-Macromolecular Crystallography
I04-Macromolecular Crystallography
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Robert P.
Law
,
Ian D.
Wall
,
Richard
Lonsdale
,
Ross P.
Hryczanek
,
Daniel
Barker
,
Tim N.
Barrett
,
Rino A.
Bit
,
John J.
Coward
,
Matthew W.
Gray
,
Darren V. S.
Green
,
Callum J.
Hall
,
Ashley P.
Hancock
,
Carl
Haslam
,
David J.
Hirst
,
Heather F.
Hryczanek
,
Jonathan P.
Hutchinson
,
Semra
Kitchen
,
David
Marcus
,
Jared
Marklew
,
Joseph
Mason
,
Nicholas D.
Measom
,
Margarete
Neu
,
Simon
Peace
,
Alex
Phillipou
,
Stephen D.
Pickett
,
Peter
Pogány
,
James
Rowedder
,
Paul
Rowland
,
Paul
Scott-Stevens
,
Gail A. L.
Seal
,
Hester
Sheehan
,
Efstratios
Stratikos
,
Chloe
Tayler
,
Jonathan A.
Taylor
,
Christopher P.
Tinworth
,
Giovanni
Vitulli
Diamond Proposal Number(s):
[37907]
Abstract: Generative design and machine learning are increasingly prevalent in medicinal chemistry. To pilot the comprehensive use of automated molecular design on a project, the BRADSHAW platform was used to optimize a series of inhibitors of Endoplasmic Reticulum Aminopeptidase 1 (ERAP1), an emerging target in cancer immunotherapy and autoimmune diseases. Through four consecutive iterations applying in silico molecular generation, property prediction and filtering, we conducted a multiparameter optimization of potency, physicochemical properties and pharmacokinetics. Continuous refinement of Machine Learning (ML) models led to improved scoring accuracy and compound quality, culminating in identification of in vitro and in vivo tool molecules. We also discuss our reflections on the pilot and integration of automated design into medicinal chemistry projects, including observations of the human factors resulting from increased use of computational design, and recommendations for future projects.
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Apr 2026
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I04-Macromolecular Crystallography
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Erin
Bradley
,
Lucia
Fusani
,
Chun-Wa
Chung
,
Peter D.
Craggs
,
Emmanuel H.
Demont
,
Philip G.
Humphreys
,
Darren J.
Mitchell
,
Alex
Phillipou
,
Inmaculada
Rioja
,
Rishi R.
Shah
,
Christopher R.
Wellaway
,
Rab K.
Prinjha
,
David S.
Palmer
,
William J.
Kerr
,
Marc
Reid
,
Ian D.
Wall
,
Rosa
Cookson
Open Access
Abstract: Small-molecule-mediated disruption of the protein–protein interactions between acetylated histone tails and the tandem bromodomains of the bromodomain and extra-terminal (BET) family of proteins is an important mechanism of action for the potential modulation of immuno-inflammatory and oncology disease. High-quality chemical probes have proven invaluable in elucidating profound BET bromodomain biology, with seminal publications of both pan- and domain-selective BET family bromodomain inhibitors enabling academic and industrial research. To enrich the toolbox of structurally differentiated N-terminal bromodomain (BD1) BET family chemical probes, this work describes an analysis of the GSK BRD4 bromodomain data set through a lipophilic efficiency lens, which enabled identification of a BD1 domain-biased benzimidazole series. Structure-guided growth targeting a key Asp/His BD1/BD2 switch enabled delivery of GSK023, a high-quality chemical probe with 300–1000-fold BET BD1 domain selectivity and a phenotypic cellular fingerprint consistent with BET bromodomain inhibition.
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Nov 2023
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I02-Macromolecular Crystallography
I03-Macromolecular Crystallography
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Francesco
Rianjongdee
,
Stephen J.
Atkinson
,
Chun-Wa
Chung
,
Paola
Grandi
,
James R. J.
Gray
,
Laura J.
Kaushansky
,
Patricia
Medeiros
,
Cassie
Messenger
,
Alex
Phillipou
,
Alex
Preston
,
Rab K.
Prinjha
,
Inmaculada
Rioja
,
Alexander L.
Satz
,
Simon
Taylor
,
Ian D.
Wall
,
Robert J.
Watson
,
Gang
Yao
,
Emmanuel H.
Demont
Abstract: Second-generation bromodomain and extra terminal (BET) inhibitors, which selectively target one of the two bromodomains in the BET proteins, have begun to emerge in the literature. These inhibitors aim to help determine the roles and functions of each domain and assess whether they can demonstrate an improved safety profile in clinical settings compared to pan-BET inhibitors. Herein, we describe the discovery of a novel BET BD2-selective chemotype using a structure-based drug design from a hit identified by DNA-encoded library technologies, showing a structural differentiation from key previously reported greater than 100-fold BD2-selective chemotypes GSK620, GSK046, and ABBV-744. Following a structure-based hypothesis for the selectivity and optimization of the physicochemical properties of the series, we identified 60 (GSK040), an in vitro ready and in vivo capable BET BD2-inhibitor of unprecedented selectivity (5000-fold) against BET BD1, excellent selectivity against other bromodomains, and good physicochemical properties. This novel chemical probe can be added to the toolbox used in the advancement of epigenetics research.
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Jul 2021
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I02-Macromolecular Crystallography
I03-Macromolecular Crystallography
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Lee A.
Harrison
,
Stephen J.
Atkinson
,
Anna
Bassil
,
Chun-Wa
Chung
,
Paola
Grandi
,
James R. J.
Gray
,
Etienne
Levernier
,
Antonia
Lewis
,
David
Lugo
,
Cassie
Messenger
,
Anne-Marie
Michon
,
Darren J.
Mitchell
,
Alex
Preston
,
Rab K.
Prinjha
,
Inmaculada
Rioja
,
Jonathan T.
Seal
,
Simon
Taylor
,
Ian D.
Wall
,
Robert J.
Watson
,
James M.
Woolven
,
Emmanuel H.
Demont
Abstract: Domain-specific BET bromodomain ligands represent an attractive target for drug discovery with the potential to unlock the therapeutic benefits of antagonizing these proteins without eliciting the toxicological aspects seen with pan-BET inhibitors. While we have reported several distinct classes of BD2 selective compounds, namely, GSK620, GSK549, and GSK046, only GSK046 shows high aqueous solubility. Herein, we describe the lead optimization of a further class of highly soluble compounds based upon a picolinamide chemotype. Focusing on achieving >1000-fold selectivity for BD2 over BD1 ,while retaining favorable physical chemical properties, compound 36 was identified as being 2000-fold selective for BD2 over BD1 (Brd4 data) with >1 mg/mL solubility in FaSSIF media. 36 represents a valuable new in vivo ready molecule for the exploration of the BD2 phenotype.
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Jul 2021
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I02-Macromolecular Crystallography
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Simon C. C.
Lucas
,
Stephen J.
Atkinson
,
Chun-Wa
Chung
,
Rob
Davis
,
Laurie
Gordon
,
Paola
Grandi
,
James J. R.
Gray
,
Thomas
Grimes
,
Alexander
Phillipou
,
Alex G.
Preston
,
Rab K.
Prinjha
,
Inmaculada
Rioja
,
Simon
Taylor
,
Nicholas C. O.
Tomkinson
,
Ian
Wall
,
Robert J.
Watson
,
James
Woolven
,
Emmanuel H.
Demont
Abstract: Herein, a series of 2,3-dihydrobenzofurans have been developed as highly potent bromo and extra-terminal domain (BET) inhibitors with 1000-fold selectivity for the second bromodomain (BD2) over the first bromodomain (BD1). Investment in the development of two orthogonal synthetic routes delivered inhibitors that were potent and selective but had raised in vitro clearance and suboptimal solubility. Insertion of a quaternary center into the 2,3-dihydrobenzofuran core blocked a key site of metabolism and improved the solubility. This led to the development of inhibitor 71 (GSK852): a potent, 1000-fold-selective, highly soluble compound with good in vivo rat and dog pharmacokinetics.
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Jul 2021
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I03-Macromolecular Crystallography
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Christopher R.
Wellaway
,
Dominique
Amans
,
Paul
Bamborough
,
Heather
Barnett
,
Rino A.
Bit
,
Jack A.
Brown
,
Neil R.
Carlson
,
Chun-Wa
Chung
,
Anthony W. J.
Cooper
,
Peter D.
Craggs
,
Robert P.
Davis
,
Tony W.
Dean
,
John P.
Evans
,
Laurie
Gordon
,
Isobel L.
Harada
,
David J.
Hirst
,
Philip G.
Humphreys
,
Katherine L.
Jones
,
Antonia J.
Lewis
,
Matthew J.
Lindon
,
Dave
Lugo
,
Mahnoor
Mahmood
,
Scott
Mccleary
,
Patricia
Medeiros
,
Darren J.
Mitchell
,
Michael
O’sullivan
,
Armelle
Le Gall
,
Vipulkumar K.
Patel
,
Chris
Patten
,
Darren L.
Poole
,
Rishi R.
Shah
,
Jane E.
Smith
,
Kayleigh A. J.
Stafford
,
Pamela J.
Thomas
,
Mythily
Vimal
,
Ian D.
Wall
,
Robert J.
Watson
,
Natalie
Wellaway
,
Gang
Yao
,
Rab K.
Prinjha
Abstract: The bromodomain and extraterminal (BET) family of bromodomain-containing proteins are important regulators of the epigenome through their ability to recognize N-acetyl lysine (KAc) post-translational modifications on histone tails. These interactions have been implicated in various disease states and, consequently, disruption of BET–KAc binding has emerged as an attractive therapeutic strategy with a number of small molecule inhibitors now under investigation in the clinic. However, until the utility of these advanced candidates is fully assessed by these trials, there remains scope for the discovery of inhibitors from new chemotypes with alternative physicochemical, pharmacokinetic, and pharmacodynamic profiles. Herein, we describe the discovery of a candidate-quality dimethylpyridone benzimidazole compound which originated from the hybridization of a dimethylphenol benzimidazole series, identified using encoded library technology, with an N-methyl pyridone series identified through fragment screening. Optimization via structure- and property-based design led to I-BET469, which possesses favorable oral pharmacokinetic properties, displays activity in vivo, and is projected to have a low human efficacious dose.
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Jan 2020
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I02-Macromolecular Crystallography
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Diamond Proposal Number(s):
[5799]
Abstract: Direct soaking of protein crystals with small-molecule fragments grouped into complementary clusters is a useful technique when assessing the potential of a new crystal system to support structure-guided drug discovery. It provides a robustness check prior to any extensive crystal screening, a double check for assay binding cutoffs and structural data for binding pockets that may or may not be picked out in assay measurements. The structural output from this technique for three novel fragment molecules identified to bind to the antibacterial target Acinetobacter baumannii undecaprenyl pyrophosphate synthase are reported, and the different physicochemical requirements of a successful antibiotic are compared with traditional medicines.
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Jan 2020
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I04-1-Macromolecular Crystallography (fixed wavelength)
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Open Access
Abstract: WONKA is a tool for the systematic analysis of an ensemble of protein–ligand structures. It makes the identification of conserved and unusual features within such an ensemble straightforward. WONKA uses an intuitive workflow to process structural co-ordinates. Ligand and protein features are summarised and then presented within an interactive web application. WONKA’s power in consolidating and summarising large amounts of data is described through the analysis of three bromodomain datasets. Furthermore, and in contrast to many current methods, WONKA relates analysis to individual ligands, from which we find unusual and erroneous binding modes. Finally the use of WONKA as an annotation tool to share observations about structures is demonstrated. WONKA is freely available to download and install locally or can be used online at http://wonka.sgc.ox.ac.uk.
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Sep 2015
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I02-Macromolecular Crystallography
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Onkar
Singh
,
Anthony
Shillings
,
Peter
Craggs
,
Ian
Wall
,
Paul
Rowland
,
Tadeusz
Skarzynski
,
Clare I.
Hobbs
,
Phil
Hardwick
,
Rob
Tanner
,
Michelle
Blunt
,
David R.
Witty
,
Kathrine J.
Smith
Abstract: ASK1, a member of the MAPK Kinase Kinase family of proteins has been shown to play a key role in cancer, neurodegeneration and cardiovascular diseases and is emerging as a possible drug target. Here we describe a ‘replacement-soaking’ method that has enabled the highthroughput X-ray structure determination of ASK1/ligand complexes. Comparison of the X-ray structures of five ASK1/ligand complexes from 3 different chemotypes illustrates that the ASK1 ATP binding site is able to accommodate a range of chemical diversity and different binding modes. The replacement-soaking system is also able to tolerate some protein flexibility. This crystal system provides a robust platform for ASK1/ligand structure determination and future structure based drug design.
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Aug 2013
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