Search Results

You searched for all publications:

with publication states 'Published (Approved)'

Search Again...

These results only include publications that have been reviewed and processed by Diamond Light Source. To also view papers that have not yet been processed click here.

You can use the folder icon under Actions to collate papers as required. You can then click on View Folder in the left-hand navigation to review and/or download your folder.

Exact matches
Related results

12 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I04-Macromolecular Crystallography	Use of human dose prediction metrics to enable discovery of AZD3470, an MTA-cooperative PRMT5 inhibitor in clinical evaluation James M. Smith , Bernard Barlaam , David Beattie , Lauren Bradshaw , Ho Man Chan , Sophie L. Cooke , Anna Cronin , Iain Cumming , Emma Dean , Judit É. Debreczeni , Iván Del Barco Barrantes , Douglas Ferguson , Davide Gianni , Michael Grondine , James T. Lynch , Lisa Mcwilliams , Shaun Moore , Piotr Raubo , Yang Qu , Graeme R. Robb , Lixiang Tan , Jelena Urosevic , Mercedes Vazquez-Chantada , Pingping Wang Journal Of Medicinal Chemistry 30 DOI: 10.1021/acs.jmedchem.6c00659 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: Inhibition of the arginine methyltransferase protein arginine methyltransferase 5 (PRMT5) has emerged as a key target for cancer therapy. Leveraging the MTAP synthetic lethality mechanism, MTA-cooperative PRMT5 inhibitors are showing promising potential as precision cancer treatments with a high therapeutic index. Herein, we report our efforts to further optimize our previously reported in vivo tool compound 1 (“AZ-PRMT5i-1”) toward a clinical candidate–quality profile, by addressing key shortcomings of this compound─limited aqueous solubility, low hERG receptor activity, and an unfavorable predicted human dose. Exploration of the terminal lactam substitution group and the central aromatic group of the isindolinone scaffold provided the key structure–activity relationship insights to meet these goals. The highest quality compounds in this series were identified by the use of a dose-to-human (D2H) automated model. These efforts resulted in the identification of 14, which shows the appropriate physicochemical properties, DMPK characteristics, and PRMT5-driven activity to be selected for progression into clinical studies.	May 2026
I04-Macromolecular Crystallography	Discovery and in vivo efficacy of AZ-PRMT5i-1, a novel PRMT5 inhibitor with high MTA cooperativity James M. Smith , Bernard Barlaam , David Beattie , Lauren Bradshaw , Ho Man Chan , Elisabetta Chiarparin , Olga Collingwood , Sophie L. Cooke , Anna Cronin , Iain Cumming , Emma Dean , Judit É. Debreczeni , Iván Del Barco Barrantes , Coura Diene , Davide Gianni , Carine Guerot , Xiaoxiao Guo , Sinem Guven , Thomas G. Hayhow , Ted Hong , Paul D. Kemmitt , Gillian M. Lamont , Scott Lamont , James T. Lynch , Lisa Mcwilliams , Shaun Moore , Piotr Raubo , Graeme R. Robb , James Robinson , James S. Scott , Bharath Srinivasan , Oliver Steward , Christopher J. Stubbs , Karl Syson , Lixiang Tan , Oliver Turner , Elizabeth Underwood , Jelena Urosevic , Mercedes Vazquez-Chantada , Amy L. Whittaker , David M. Wilson , Jon J. Winter-Holt Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.4c00097 Show Abstract ▼ Abstract: PRMT5, a type 2 arginine methyltransferase, has a critical role in regulating cell growth and survival in cancer. With the aim of developing MTA-cooperative PRMT5 inhibitors suitable for MTAP-deficient cancers, herein we report our efforts to develop novel “MTA-cooperative” compounds identified through a high-throughput biochemical screening approach. Optimization of hits was achieved through structure-based design with a focus on improvement of oral drug-like properties. Bioisosteric replacement of the original thiazole guanidine headgroup, spirocyclization of the isoindolinone amide scaffold to both configurationally and conformationally lock the bioactive form, and fine-tuning of the potency, MTA cooperativity, and DMPK properties through specific substitutions of the azaindole headgroup were conducted. We have identified an orally available in vivo lead compound, 28 (“AZ-PRMT5i-1”), which shows sub-10 nM PRMT5 cell potency, >50-fold MTA cooperativity, suitable DMPK properties for oral dosing, and significant PRMT5-driven in vivo efficacy in several MTAP-deficient preclinical cancer models.	Jul 2024
	The CCP 4 suite: integrative software for macromolecular crystallography Jon Agirre , Mihaela Atanasova , Haroldas Bagdonas , Charles B. Ballard , Arnaud Basle , James Beilsten-Edmands , Rafael J. Borges , David G. Brown , J. Javier Burgos-Marmol , John M. Berrisford , Paul S. Bond , Iracema Caballero , Lucrezia Catapano , Grzegorz Chojnowski , Atlanta G. Cook , Kevin D. Cowtan , Tristan I. Croll , Judit É. Debreczeni , Nicholas E. Devenish , Eleanor J. Dodson , Tarik R. Drevon , Paul Emsley , Gwyndaf Evans , Phil R. Evans , Maria Fando , James Foadi , Luis Fuentes-Montero , Elspeth F. Garman , Markus Gerstel , Richard J. Gildea , Kaushik Hatti , Maarten L. Hekkelman , Philipp Heuser , Soon Wen Hoh , Michael A. Hough , Huw T. Jenkins , Elisabet Jiménez , Robbie P. Joosten , Ronan M. Keegan , Nicholas Keep , Eugene B. Krissinel , Petr Kolenko , Oleg Kovalevskiy , Victor S. Lamzin , David M. Lawson , Andrey Lebedev , Andrew G. W. Leslie , Bernhard Lohkamp , Fei Long , Martin Maly , Airlie Mccoy , Stuart J. Mcnicholas , Ana Medina , Claudia Millán , James W. Murray , Garib N. Murshudov , Robert A. Nicholls , Martin E. M. Noble , Robert Oeffner , Navraj S. Pannu , James M. Parkhurst , Nicholas Pearce , Joana Pereira , Anastassis Perrakis , Harold R. Powell , Randy J. Read , Daniel J. Rigden , William Rochira , Massimo Sammito , Filomeno Sanchez Rodriguez , George M. Sheldrick , Kathryn L. Shelley , Felix Simkovic , Adam J. Simpkin , Pavol Skubak , Egor Sobolev , Roberto A. Steiner , Kyle Stevenson , Ivo Tews , Jens M. H. Thomas , Andrea Thorn , Josep Triviño Valls , Ville Uski , Isabel Uson , Alexei Vagin , Sameer Velankar , Melanie Vollmar , Helen Walden , David Waterman , Keith S. Wilson , Martyn Winn , Graeme Winter , Marcin Wojdyr , Keitaro Yamashita Acta Crystallographica Section D Structural Biology 79, 449 - 461 DOI: 10.1107/S2059798323003595 Open Access Show Abstract ▼ Abstract: The Collaborative Computational Project No. 4 (CCP4) is a UK-led international collective with a mission to develop, test, distribute and promote software for macromolecular crystallography. The CCP4 suite is a multiplatform collection of programs brought together by familiar execution routines, a set of common libraries and graphical interfaces. The CCP4 suite has experienced several considerable changes since its last reference article, involving new infrastructure, original programs and graphical interfaces. This article, which is intended as a general literature citation for the use of the CCP4 software suite in structure determination, will guide the reader through such transformations, offering a general overview of the new features and outlining future developments. As such, it aims to highlight the individual programs that comprise the suite and to provide the latest references to them for perusal by crystallographers around the world.	Jun 2023
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	KRAS-specific inhibition using a DARPin binding to a site in the allosteric lobe Nicolas Bery , Sandrine Legg , Judit Debreczeni , Jason Breed , Kevin Embrey , Christopher Stubbs , Paulina Kolasinska-Zwierz , Nathalie Barrett , Rose Marwood , Jo Watson , Jon Tart , Ross Overman , Ami Miller , Christopher Phillips , Ralph Minter , Terence H. Rabbitts Nature Communications 10, 2607 DOI: 10.1038/s41467-019-10419-2 Open Access Show Abstract ▼ Abstract: Inhibiting the RAS oncogenic protein has largely been through targeting the switch regions that interact with signalling effector proteins. Here, we report designed ankyrin repeat proteins (DARPins) macromolecules that specifically inhibit the KRAS isoform by binding to an allosteric site encompassing the region around KRAS-specific residue histidine 95 at the helix α3/loop 7/helix α4 interface. We show that these DARPins specifically inhibit KRAS/effector interactions and the dependent downstream signalling pathways in cancer cells. Binding by the DARPins at that region influences KRAS/effector interactions in different ways, including KRAS nucleotide exchange and inhibiting KRAS dimerization at the plasma membrane. These results highlight the importance of targeting the α3/loop 7/α4 interface, a previously untargeted site in RAS, for specifically inhibiting KRAS function.	Jun 2019
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	A study of the reactivity of S (VI) –F containing warheads with nucleophilic amino-acid side chains under physiological conditions H. Mukherjee , J. Debreczeni , J. Breed , S. Tentarelli , B. Aquila , J. E. Dowling , A. Whitty , N. P. Grimster Organic & Biomolecular Chemistry 15, 9685 - 9695 DOI: 10.1039/C7OB02028G Show Abstract ▼ Abstract: Sulfonyl fluorides (SFs) have recently emerged as a promising warhead for the targeted covalent modification of proteins. Despite numerous examples of the successful deployment of SFs as covalent probe compounds, a detailed exploration of the factors influencing the stability and reactivity of SFs has not yet appeared. In this work we present an extensive study on the influence of steric and electronic factors on the reactivity and stability of the SF and related SVI–F groups. While SFs react rapidly with N-acetylcysteine, the resulting adducts were found to be unstable, rendering SFs inappropriate for the durable covalent inhibition of cysteine residues. In contrast, SFs afforded stable adducts with both N-acetyltyrosine and N-acetyllysine; furthermore, we show that the reactivity of arylsulfonyl fluorides towards these nucleophilic amino acids can be predictably modulated by adjusting the electronic properties of the warhead. These trends were largely conserved when the covalent reaction occurred within a protein binding pocket. We have also obtained a crystal structure depicting covalent modification of the catalytic lysine of a tyrosine kinase (FGFR1) by the ATP analog 5′-O-3-((fluorosulfonyl)benzoyl)adenosine (m-FSBA). Highly reactive warheads were demonstrated to be unstable with respect to hydrolysis in buffered aqueous solutions, indicating that warhead reactivity must be carefully tuned to provide optimal rates of protein modification. Our results demonstrate that the reactivity of SFs complements that of more commonly studied acrylamides, and we hope that this work spurs the rational design of novel SF-containing covalent probe compounds and inhibitors, particularly in cases where a suitably positioned cysteine residue is not present.	Oct 2017
I03-Macromolecular Crystallography	A high-throughput screening triage workflow to authenticate a novel series of PFKFB3 inhibitors Stephen A. St-Gallay , Neil Bennett , Susan E. Critchlow , Nicola Curtis , Gareth Davies , Judit Debreczeni , Nicola Evans , Ian Hardern , Geoff Holdgate , Neil P. Jones , Lindsey Leach , Sarita Maman , Sheila Mcloughlin , Marian Preston , Laurent Rigoreau , Andrew Thomas , Andrew P. Turnbull , Graeme Walker , Jarrod Walsh , Richard A. Ward , Ed Wheatley , Jon Winter-Holt Slas Discovery: Advancing Life Sciences R&d 27 DOI: 10.1177/2472555217732289 Diamond Proposal Number(s): [5735] Open Access Show Abstract ▼ Abstract: A high-throughput screen (HTS) of human 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) resulted in several series of compounds with the potential for further optimization. Informatics was used to identify active chemotypes with lead-like profiles and remove compounds that commonly occurred as actives in other HTS screens. The activities were confirmed with IC50 measurements from two orthogonal assay technologies, and further analysis of the Hill slopes and comparison of the ratio of IC50 values at 10 times the enzyme concentration were used to identify artifact compounds. Several series of compounds were rejected as they had both high slopes and poor ratios. A small number of compounds representing the different leading series were assessed using isothermal titration calorimetry, and the X-ray crystal structure of the complex with PFKFB3 was solved. The orthogonal assay technology and isothermal calorimetry were demonstrated to be unreliable in identifying false-positive compounds in this case. Presented here is the discovery of the dihydropyrrolopyrimidinone series of compounds as active and novel inhibitors of PFKFB3, shown by X-ray crystallography to bind to the adenosine triphosphate site. The crystal structures of this series also reveal it is possible to flip the binding mode of the compounds, and the alternative orientation can be driven by a sigma-hole interaction between an aromatic chlorine atom and a backbone carbonyl oxygen. These novel inhibitors will enable studies to explore the role of PFKFB3 in driving the glycolytic phenotype of tumors.	Sep 2017
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Structural and functional characterization of a DARPin which inhibits Ras nucleotide exchange Sandrine Guillard , Paulina Kolasinska-Zwierz , Judit Debreczeni , Jason Breed , Jing Zhang , Nicolas Bery , Rose Marwood , Jon Tart , Ross Overman , Pawel Stocki , Bina Mistry , Christopher Phillips , Terence Rabbitts , Ronald Jackson , Ralph Minter Nature Communications 8 DOI: 10.1038/ncomms16111 Diamond Proposal Number(s): [17180] Open Access Show Abstract ▼ Abstract: Ras mutations are the oncogenic drivers of many human cancers and yet there are still no approved Ras-targeted cancer therapies. Inhibition of Ras nucleotide exchange is a promising new approach but better understanding of this mechanism of action is needed. Here we describe an antibody mimetic, DARPin K27, which inhibits nucleotide exchange of Ras. K27 binds preferentially to the inactive Ras GDP form with a Kd of 4 nM and structural studies support its selectivity for inactive Ras. Intracellular expression of K27 significantly reduces the amount of active Ras, inhibits downstream signalling, in particular the levels of phosphorylated ERK, and slows the growth in soft agar of HCT116 cells. K27 is a potent, non-covalent inhibitor of nucleotide exchange, showing consistent effects across different isoforms of Ras, including wild-type and oncogenic mutant forms.	Jul 2017
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Structure-guided discovery of potent and selective inhibitors of ERK1/2 from a modestly active and promiscuous chemical start point Richard A Ward , Paul A. Bethel , Calum Cook , Emma Davies , Judit E. Debreczeni , Gary Fairley , Lyman Feron , Vikki Flemington , Mark A. Graham , Ryan Greenwood , Nicola Griffin , Lyndsey Hanson , Philip Hopcroft , Tina D. Howard , Julian Hudson , Michael James , Clifford D. Jones , Christopher R Jones , Scott Lamont , Richard James Lewis , Nicola Lindsay , Karen Roberts , Iain Simpson , Steve St-Gallay , Steve Swallow , Jia Tang , Michael Tonge , Zhenhua Wang , Baochang Zhai Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.7b00267 Show Abstract ▼ Abstract: There are a number of small molecule inhibitors targeting the RAS/RAF/MEK/ERK signaling pathway either approved or in clinical development for oncology across a range of disease indications. The inhibition of ERK1/2 is of significant current interest as cell lines with acquired resistance to BRAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition in pre-clinical models. This manuscript reports on our recent work to identify novel, potent and selective reversible ERK1/2 inhibitors from a low molecular weight, modestly active and highly promiscuous chemical starting point 4. To guide and inform the evolution of this series, inhibitor binding mode information from x-ray crystal structures was critical in the rapid exploration of this template to compound 35, which was active when tested in in vivo anti tumour efficacy experiments.	Apr 2017
I04-Macromolecular Crystallography	Structural basis of Lewisb antigen binding by the Helicobacter pylori adhesin BabA N. Hage , T. Howard , C. Phillips , C. Brassington , R. Overman , J. Debreczeni , P. Gellert , S. Stolnik , G. S. Winkler , F. H. Falcone Science Advances 1, e1500315 - e1500315 DOI: 10.1126/sciadv.1500315 PMID: 26601230 Open Access Show Abstract ▼ Abstract: Helicobacter pylori is a leading cause of peptic ulceration and gastric cancer worldwide. To achieve colonization of the stomach, this Gram-negative bacterium adheres to Lewisb (Leb) antigens in the gastric mucosa using its outer membrane protein BabA. Structural information for BabA has been elusive, and thus, its molecular mechanism for recognizing Leb antigens remains unknown. We present the crystal structure of the extracellular domain of BabA, from H. pylori strain J99, in the absence and presence of Leb at 2.0- and 2.1-Å resolutions, respectively. BabA is a predominantly α-helical molecule with a markedly kinked tertiary structure containing a single, shallow Leb binding site at its tip within a β-strand motif. No conformational change occurs in BabA upon binding of Leb, which is characterized by low affinity under acidic [KD (dissociation constant) of ~227 μM] and neutral (KD of ~252 μM) conditions. Binding is mediated by a network of hydrogen bonds between Leb Fuc1, GlcNAc3, Fuc4, and Gal5 residues and a total of eight BabA amino acids (C189, G191, N194, N206, D233, S234, S244, and T246) through both carbonyl backbone and side-chain interactions. The structural model was validated through the generation of two BabA variants containing N206A and combined D233A/S244A substitutions, which result in a reduction and complete loss of binding affinity to Leb, respectively. Knowledge of the molecular basis of Leb recognition by BabA provides a platform for the development of therapeutics targeted at inhibiting H. pylori adherence to the gastric mucosa.	Aug 2015
I02-Macromolecular Crystallography	Structure-guided design of highly selective and potent covalent inhibitors of ERK1/2 Richard A. Ward , Nicola Colclough , Mairi Challinor , Judit E. Debreczeni , Kay Eckersley , Gary Fairley , Lyman Feron , Vikki Flemington , Mark A. Graham , Ryan Greenwood , Philip Hopcroft , Tina D. Howard , Michael James , Clifford D. Jones , Christopher R. Jones , Jonathan Renshaw , Karen Roberts , Lindsay Snow , Michael Tonge , Kay Yeung Journal Of Medicinal Chemistry 58 (11), 4790 - 4801 DOI: 10.1021/acs.jmedchem.5b00466 PMID: 25977981 Show Abstract ▼ Abstract: The RAS/RAF/MEK/ERK signaling pathway has been targeted with a number of small molecule inhibitors in oncology clinical development across multiple disease indications. Importantly, cell lines with acquired resistance to B-RAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition by small molecule inhibitors. There are a number of selective, noncovalent ERK1/2 inhibitors reported along with the promiscuous hypothemycin (and related analogues) that act via a covalent mechanism of action. This article reports the identification of multiple series of highly selective covalent ERK1/2 inhibitors informed by structure-based drug design (SBDD). As a starting point for these covalent inhibitors, reported ERK1/2 inhibitors and a chemical series identified via high-throughput screening were exploited. These approaches resulted in the identification of selective covalent tool compounds for potential in vitro and in vivo studies to assess the risks and or benefits of targeting this pathway through such a mechanism of action.	Jun 2015

Publications Database

Search Results

You searched for all publications:

Search Again...

Subject Areas (check all that apply) select all

Instruments used to collect data (check all that apply) select all

Collaborations involved (check all that apply) select all

Diamond Offline Facilities used

Relevant Technical Areas (check all that apply) select all

Menu for Anonymous User