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

10 items found (0 items not approved), displaying all items.1

Instruments / Technical Area	Publication Details	Published
I03-Macromolecular Crystallography	Discovery of 6-fluoro-5-{4-[(5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide (AZD9574): A CNS-penetrant, PARP1-selective inhibitor Jeffrey W. Johannes , Amber Y. S. Balazs , Derek Barratt , Michal Bista , Matthew D. Chuba , Sabina Cosulich , Susan E. Critchlow , Sébastien L. Degorce , Paolo Di Fruscia , Scott D. Edmondson , Kevin J. Embrey , Stephen Fawell , Avipsa Ghosh , Sonja J. Gill , Anders Gunnarsson , Sudhir M. Hande , Tom D. Heightman , Paul Hemsley , Giuditta Illuzzi , Jordan Lane , Carrie J. B. Larner , Elisabetta Leo , Lina Liu , Andrew Madin , Lisa Mcwilliams , Mark J. O’connor , Jonathan P. Orme , Fiona Pachl , Martin J. Packer , Xiaohui Pei , Andy Pike , Marianne Schimpl , Hongyao She , Anna D. Staniszewska , Verity Talbot , Elizabeth Underwood , Jeffrey G. Varnes , Lin Xue , Tieguang Yao , Ke Zhang , Andrew X. Zhang , Xiaolan Zheng Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.4c01725 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: PARP inhibitors have attracted considerable interest in drug discovery due to the clinical success of first-generation agents such as olaparib, niraparib, rucaparib, and talazoparib. Their success lies in their ability to trap PARP to DNA; however, first-generation PARP inhibitors were not strictly optimized for trapping nor for selectivity among the PARP enzyme family. Previously we described the discovery of the second-generation PARP inhibitor AZD5305, a selective PARP1-DNA trapper. AZD5305 maintained the antitumor efficacy of first-generation PARP inhibitors while exhibiting lower hematological toxicity. Recently, there has been interest in central nervous system (CNS)-penetrant PARP inhibitors for CNS malignancies and other neurological conditions; however, AZD5305 is not CNS penetrant. Herein we describe the discovery and optimization of a series of CNS-penetrant, PARP1-selective inhibitors and PARP1-DNA trappers, culminating in the discovery of AZD9574, a compound that maintains the PARP1 selectivity of AZD5305 with improved permeability, reduced efflux, and increased CNS penetration.	Dec 2024
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
I04-Macromolecular Crystallography	Identification of novel potent NSD2-PWWP1 ligands using structure-based design and computational approaches Luca Carlino , Peter C. Astles , Bryony Ackroyd , Afshan Ahmed , Christina Chan , Gavin W. Collie , Ian L. Dale , Daniel H. O’donovan , Caroline Fawcett , Paolo Di Fruscia , Andrea Gohlke , Xiaoxiao Guo , Jessie Hao-Ru Hsu , Bethany Kaplan , Alexander G. Milbradt , Sarah Northall , Dušan Petrović , Emma L. Rivers , Elizabeth Underwood , Alice Webb Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.4c00215 Show Abstract ▼ Abstract: Dysregulation of histone methyl transferase nuclear receptor-binding SET domain 2 (NSD2) has been implicated in several hematological and solid malignancies. NSD2 is a large multidomain protein that carries histone writing and histone reading functions. To date, identifying inhibitors of the enzymatic activity of NSD2 has proven challenging in terms of potency and SET domain selectivity. Inhibition of the NSD2-PWWP1 domain using small molecules has been considered as an alternative approach to reduce NSD2-unregulated activity. In this article, we present novel computational chemistry approaches, encompassing free energy perturbation coupled to machine learning (FEP/ML) models as well as virtual screening (VS) activities, to identify high-affinity NSD2 PWWP1 binders. Through these activities, we have identified the most potent NSD2-PWWP1 binder reported so far in the literature: compound 34 (pIC50 = 8.2). The compounds identified herein represent useful tools for studying the role of PWWP1 domains for inhibition of human NSD2.	May 2024
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	Discovery of 5-{4-[(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}- N -methylpyridine-2-carboxamide (AZD5305): A PARP1–DNA Trapper with High Selectivity for PARP1 over PARP2 and Other PARPs Jeffrey W. Johannes , Amber Balazs , Derek Barratt , Michal Bista , Matthew D. Chuba , Sabina Cosulich , Susan E. Critchlow , Sébastien L. Degorce , Paolo Di Fruscia , Scott D. Edmondson , Kevin Embrey , Stephen Fawell , Avipsa Ghosh , Sonja J. Gill , Anders Gunnarsson , Sudhir M. Hande , Tom D. Heightman , Paul Hemsley , Giuditta Illuzzi , Jordan Lane , Carrie Larner , Elisabetta Leo , Lina Liu , Andrew Madin , Scott Martin , Lisa Mcwilliams , Mark J. O'Connor , Jonathan P. Orme , Fiona Pachl , Martin J. Packer , Xiaohui Pei , Andrew Pike , Marianne Schimpl , Hongyao She , Anna D. Staniszewska , Verity Talbot , Elizabeth Underwood , Jeffrey G. Varnes , Lin Xue , Tieguang Yao , Ke Zhang , Andrew X. Zhang , Xiaolan Zheng Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c01012 Diamond Proposal Number(s): [14631, 17180, 20015] Show Abstract ▼ Abstract: Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some have failed in combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP inhibitors lack selectivity for PARP1 over PARP2 and some other 16 PARP family members, and we hypothesized that this could contribute to toxicity. Recent literature has demonstrated that PARP1 inhibition and PARP1–DNA trapping are key for driving efficacy in a BRCA mutant background. Herein, we describe the structure- and property-based design of 25 (AZD5305), a potent and selective PARP1 inhibitor and PARP1–DNA trapper with excellent in vivo efficacy in a BRCA mutant HBCx-17 PDX model. Compound 25 is highly selective for PARP1 over other PARP family members, with good secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species, with reduced effects on human bone marrow progenitor cells in vitro.	Sep 2021
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Fragment-based design of a potent MAT2a inhibitor and in vivo evaluation in an MTAP null xenograft model Claudia De Fusco , Marianne Schimpl , Ulf Börjesson , Tony Cheung , Iain Collie , Laura Evans , Priyanka Narasimhan , Christopher Stubbs , Mercedes Vazquez-Chantada , David J. Wagner , Michael Grondine , Matthew G. Sanders , Sharon Tentarelli , Elizabeth Underwood , Argyrides Argyrou , James M. Smith , James T. Lynch , Elisabetta Chiarparin , Graeme Robb , Sharan K. Bagal , James S. Scott Journal Of Medicinal Chemistry 64, 6814 - 6826 DOI: 10.1021/acs.jmedchem.1c00067 Open Access Show Abstract ▼ Abstract: MAT2a is a methionine adenosyltransferase that synthesizes the essential metabolite S-adenosylmethionine (SAM) from methionine and ATP. Tumors bearing the co-deletion of p16 and MTAP genes have been shown to be sensitive to MAT2a inhibition, making it an attractive target for treatment of MTAP-deleted cancers. A fragment-based lead generation campaign identified weak but efficient hits binding in a known allosteric site. By use of structure-guided design and systematic SAR exploration, the hits were elaborated through a merging and growing strategy into an arylquinazolinone series of potent MAT2a inhibitors. The selected in vivo tool compound 28 reduced SAM-dependent methylation events in cells and inhibited proliferation of MTAP-null cells in vitro. In vivo studies showed that 28 was able to induce antitumor response in an MTAP knockout HCT116 xenograft model.	May 2021
I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Generating selective leads for Mer kinase inhibitors - example of a comprehensive lead-generation strategy J. Willem M. Nissink , Sana Bazzaz , Carolyn Blackett , Matthew A. Clark , Olga Collingwood , Jeremy S. Disch , Diana Gikunju , Kristin Goldberg , John P. Guilinger , Elizabeth Hardaker , Edward J. Hennessy , Rachael Jetson , Anthony D. Keefe , William Mccoull , Lindsay Mcmurray , Allison Olszewski , Ross Overman , Alexander Pflug , Marian Preston , Philip B. Rawlins , Emma Rivers , Marianne Schimpl , Paul Smith , Caroline Truman , Elizabeth Underwood , Juli Warwicker , Jon Winter-Holt , Simon Woodcock , Ying Zhang Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c01904 Show Abstract ▼ Abstract: Mer is a member of the TAM (Tyro3, Axl, Mer) kinase family that has been associated with cancer progression, metastasis, and drug resistance. Their essential function in immune homeostasis has prompted an interest in their role as modulators of antitumor immune response in the tumor microenvironment. Here we illustrate the outcomes of an extensive lead-generation campaign for identification of Mer inhibitors, focusing on the results from concurrent, orthogonal high-throughput screening approaches. Data mining, HT (high-throughput), and DECL (DNA-encoded chemical library) screens offered means to evaluate large numbers of compounds. We discuss campaign strategy and screening outcomes, and exemplify series resulting from prioritization of hits that were identified. Concurrent execution of HT and DECL screening successfully yielded a large number of potent, selective, and novel starting points, covering a range of selectivity profiles across the TAM family members and modes of kinase binding, and offered excellent start points for lead development.	Mar 2021
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Dynamics of the HD regulatory subdomain of PARP-1; substrate access and allostery in PARP activation and inhibition Tom E. H. Ogden , Ji-Chun Yang , Marianne Schimpl , Laura E. Easton , Elizabeth Underwood , Philip b. Rawlins , Michael m. Mccauley , Marie-France Langelier , John m. Pascal , Kevin j. Embrey , David Neuhaus Nucleic Acids Research 25 DOI: 10.1093/nar/gkab020 Diamond Proposal Number(s): [17180, 20015] Open Access Show Abstract ▼ Abstract: PARP-1 is a key early responder to DNA damage in eukaryotic cells. An allosteric mechanism links initial sensing of DNA single-strand breaks by PARP-1’s F1 and F2 domains via a process of further domain assembly to activation of the catalytic domain (CAT); synthesis and attachment of poly(ADP-ribose) (PAR) chains to protein sidechains then signals for assembly of DNA repair components. A key component in transmission of the allosteric signal is the HD subdomain of CAT, which alone bridges between the assembled DNA-binding domains and the active site in the ART subdomain of CAT. Here we present a study of isolated CAT domain from human PARP-1, using NMR-based dynamics experiments to analyse WT apo-protein as well as a set of inhibitor complexes (with veliparib, olaparib, talazoparib and EB-47) and point mutants (L713F, L765A and L765F), together with new crystal structures of the free CAT domain and inhibitor complexes. Variations in both dynamics and structures amongst these species point to a model for full-length PARP-1 activation where first DNA binding and then substrate interaction successively destabilise the folded structure of the HD subdomain to the point where its steric blockade of the active site is released and PAR synthesis can proceed.	Jan 2021
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I04-Macromolecular Crystallography	A-loop interactions in Mer tyrosine kinase give rise to inhibitors with two-step mechanism and long residence time of binding Alexander Pflug , Marianne Schimpl , J. Willem M. Nissink , Ross C. Overman , Philip B. Rawlins , Caroline Truman , Elizabeth Underwood , Juli Warwicker , Jon J. Winter-Holt , William Mccoull Biochemical Journal DOI: 10.1042/BCJ20200735 Diamond Proposal Number(s): [14631, 17180, 20015] Open Access Show Abstract ▼ Abstract: The activation loop (A-loop) plays a key role in regulating the catalytic activity of protein kinases. Phosphorylation in this region enhances the phosphoryl transfer rate of the kinase domain and increases its affinity for ATP. Furthermore, the A-loop possesses autoinhibitory functions in some kinases, where it collapses onto the protein surface and blocks substrate binding when unphosphorylated. Due to its flexible nature, the A-loop is usually disordered and untraceable in kinase domain crystal structures. The resulting lack of structural information is regrettable as it impedes the design of drug A-loop contacts, which have proven favourable in multiple cases. Here we characterize the binding with A-loop engagement between type 1.5 kinase inhibitor ‘example 172’ (EX172) and Mer tyrosine kinase (MerTK). With the help of crystal structures and binding kinetics we portray how the recruitment of the A-loop elicits a two-step binding mechanism which results in a drug-target complex characterized by high affinity and long residence time. In addition, the type 1.5 compound possesses excellent kinome selectivity and a remarkable preference for the phosphorylated over the dephosphorylated form of MerTK. We discuss these unique characteristics in the context of known type 1 and type 2 inhibitors and highlight opportunities for future kinase inhibitor design.	Oct 2020
I02-Macromolecular Crystallography	Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2 Neil Justin , Ying Zhang , Cataldo Tarricone , Stephen R. Martin , Shuyang Chen , Elizabeth Underwood , Valeria De Marco , Lesley F. Haire , Philip A. Walker , Danny Reinberg , Jon R. Wilson , Steven Gamblin Nature Communications 7 DOI: 10.1038/ncomms11316 Diamond Proposal Number(s): [9826] Open Access Show Abstract ▼ Abstract: Polycomb repressive complex 2 (PRC2) silences gene expression through trimethylation of K27 of histone H3 (H3K27me3) via its catalytic SET domain. A missense mutation in the substrate of PRC2, histone H3K27M, is associated with certain pediatric brain cancers and is linked to a global decrease of H3K27me3 in the affected cells thought to be mediated by inhibition of PRC2 activity. We present here the crystal structure of human PRC2 in complex with the inhibitory H3K27M peptide bound to the active site of the SET domain, with the methionine residue located in the pocket that normally accommodates the target lysine residue. The structure and binding studies suggest a mechanism for the oncogenic inhibition of H3K27M. The structure also reveals how binding of repressive marks, like H3K27me3, to the EED subunit of the complex leads to enhancement of the catalytic efficiency of the SET domain and thus the propagation of this repressive histone modification.	Apr 2016
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Structural basis of AMPK regulation by small molecule activators Bing Xiao , Matthew J. Sanders , David Carmena , Nicola J. Bright , Lesley F. Haire , Elizabeth Underwood , Bhakti R. Patel , Richard B. Heath , Phillip A. Walker , Stefan Hallen , Fabrizio Giordanetto , Stephen R. Martin , David Carling , Steven Gamblin Nature Communications 4 DOI: 10.1038/ncomms4017 PMID: 24352254 Diamond Proposal Number(s): [7707] Open Access Show Abstract ▼ Abstract: AMP-activated protein kinase (AMPK) plays a major role in regulating cellular energy balance by sensing and responding to increases in AMP/ADP concentration relative to ATP. Binding of AMP causes allosteric activation of the enzyme and binding of either AMP or ADP promotes and maintains the phosphorylation of threonine 172 within the activation loop of the kinase. AMPK has attracted widespread interest as a potential therapeutic target for metabolic diseases including type 2 diabetes and, more recently, cancer. A number of direct AMPK activators have been reported as having beneficial effects in treating metabolic diseases, but there has been no structural basis for activator binding to AMPK. Here we present the crystal structure of human AMPK in complex with a small molecule activator that binds at a site between the kinase domain and the carbohydrate-binding module, stabilising the interaction between these two components. The nature of the activator-binding pocket suggests the involvement of an additional, as yet unidentified, metabolite in the physiological regulation of AMPK. Importantly, the structure offers new opportunities for the design of small molecule activators of AMPK for treatment of metabolic disorders.	Dec 2013

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