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176 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2, 3, 4, 5, 6, 7, 8 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I03-Macromolecular Crystallography	Discovery of a bromodomain and extraterminal inhibitor with a low predicted human dose through synergistic use of encoded library technology and fragment screening 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 Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b01670 Show Abstract ▼ 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.	Jan 2020
I03-Macromolecular Crystallography	The discovery of 7-methyl-2-[(7-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (AZD7648), a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor Frederick Woolf Goldberg , M. Raymond V. Finlay , Attilla Ting , David Beattie , Gillian Lamont , Charlene Fallan , Gail Wrigley , Marianne Schimpl , Martin R. Howard , Beth Williamson , Mercedes Vazquez-chantada , Derek Barratt , Barry Davies , Elaine Cadogan , Antonio Ramos Montoya , Emma Dean Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b01684 Show Abstract ▼ Abstract: DNA-PK is a key component within the DNA damage response, as it is responsible for recognizing and repairing double-strand DNA breaks (DSBs) via non-homologous end joining. Historically it has been challenging to identify inhibitors of the DNA-PK catalytic subunit (DNA-PKcs) with good selectivity versus the structurally related PI3 (lipid) and PI3K-related protein kinases. We screened our corporate collection for DNA-PKcs inhibitors with good PI3 kinase selectivity, identifying compound 1. Optimization focused on further improving selectivity whilst improving physical and pharmacokinetic properties, notably co-optimization of permeability and metabolic stability, to identify compound 16 (AZD7648). Compound 16 had no significant off-targets in the protein kinome, and only weak activity versus PI3Kα/γ lipid kinases. Monotherapy activity in murine xenograft models was observed, and regressions were observed when combined with inducers of DSBs (doxorubicin or irradiation) or PARP inhibition (olaparib). These data support progression into clinical studies (NCT03907969).	Dec 2019
I24-Microfocus Macromolecular Crystallography	Comparison of orexin 1 and orexin 2 ligand binding modes using X-ray crystallography and computational analysis Mathieu Rappas , Ammar Ali , Kirstie A. Bennett , Jason D. Brown , Sarah J. Bucknell , Miles Congreve , Robert M. Cooke , Gabriella Cseke , Chris De Graaf , Andrew S. Dore , James C. Errey , Ali Jazayeri , Fiona H. Marshall , Jonathan S. Mason , Richard Mould , Jayesh C. Patel , Benjamin G. Tehan , Malcolm Weir , John A. Christopher Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b01787 Diamond Proposal Number(s): [5788, 20025, 12425, 5999, 5788, 17185, 20025] Show Abstract ▼ Abstract: The orexin system, which consists of the two G protein-coupled receptors OX1 and OX2, activated by the neuropeptides OX-A and OX-B, is firmly established as a key regulator of behavioural arousal, sleep and wakefulness, and has been an area of intense research effort over the past two decades. X-ray structures of the receptors in complex with ten new antagonist ligands from diverse chemotypes are presented, which complement the existing structural information for the system and highlight the critical importance of lipophilic hotspots and water molecules for these peptidergic GPCR targets. Learnings from the structural information regarding the utility of pharmacophore models and how selectivity between OX1 and OX2 can be achieved are discussed.	Dec 2019
I04-Macromolecular Crystallography	Discovery of a potent and selective oral inhibitor of ERK1/2 (AZD0364) that is efficacious in both monotherapy and combination therapy in models of non-small cell lung cancer (NSCLC) Richard A Ward , Mark J Anderton , Paul A. Bethel , Jason Breed , Calum Cook , Emma Davies , Andrew Dobson , Zhiqiang Dong , Gary Fairley , Paul Farrington , Lyman J. Feron , Vikki Flemington , Francis D Gibbons , Mark A. Graham , Ryan David Robert Greenwood , Lyndsey Hanson , Philip Hopcroft , Rachel Howells , Julian Hudson , Michael James , Clifford D. Jones , Christopher Jones , Yongchao Li , Scott Lamont , Richard James Lewis , Nicola A. Lindsay , James Francis Mccabe , Thomas M. Mcguire , Philip B. Rawlins , Karen Roberts , Linda Sandin , Iain Simpson , Steve Swallow , Jia Tang , Gary Tomkinson , Michael Tonge , Zhenhua Wang , Baochang Zhai Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b01295 Diamond Proposal Number(s): [20015, 17180] Show Abstract ▼ Abstract: The RAS/MAPK pathway is a major driver of oncogenesis and is dysregulated in approximately 30% of human cancers, primarily by mutations in the BRAF or RAS genes. The extracellular-signal-regulated kinases (ERK1 and ERK2) serve as central nodes within this pathway. The feasibility of targeting the RAS/MAPK pathway has been demonstrated by the clinical responses observed through the use of BRAF and MEK inhibitors in BRAF V600E/K metastatic melanoma, however resistance frequently develops. Importantly, ERK1/2 inhibition may have clinical utility in overcoming acquired resistance to RAF and MEK inhibitors where RAS/MAPK pathway reactivation has occurred, such as relapsed BRAF V600E/K melanoma. We describe our structure-based design approach leading to the discovery of AZD0364, a potent and selective inhibitor of ERK1 and ERK2. AZD0364 exhibits high cellular potency (IC50 = 6 nM) and excellent physico-chemical and absorption, distribution, metabolism, and excretion (ADME) properties and has demonstrated encouraging anti-tumour activity in pre-clinical models.	Nov 2019
	Discovery of taniborbactam (VNRX-5133): A broad-spectrum serine- and metallo-β-lactamase inhibitor for carbapenem-resistant bacterial infections Bin Liu , Robert E. Lee Trout , Guo-hua Chu , Daniel Mcgarry , Randy W Jackson , Jodie Hamrick , Denis Daigle , Susan Cusick , Cecilia Pozzi , Filomena De Luca , Manuela Benvenuti , Stefano Mangani , Jean-denis Docquier , William J. Weiss , Daniel C. Pevear , Luigi Xerri , Christopher J. Burns Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b01518 Show Abstract ▼ Abstract: A major resistance mechanism in Gram-negative bacteria is the production of β-lactamase enzymes. Originally recognized for their ability to hydrolyze penicillins, emergent β-lactamases can now confer resistance to other β-lactam drugs, including both cephalosporins and carbapenems. The emergence and global spread of β-lactamase-producing multi-drug-resistant "superbugs" has caused increased alarm within the medical community due to the high mortality rate associated with these difficult-to-treat bacterial infections. To address this unmet medical need, we initiated an iterative program combining medicinal chemistry, structural biology, biochemical testing and microbiological profiling to identify broad-spectrum inhibitors of both serine- and metallo-β-lactamase enzymes. Lead optimization, beginning with narrower-spectrum, weakly active compounds provided 20 (VNRX-5133, taniborbactam), a boronic acid-containing pan-spectrum β-lactamase inhibitor. In vitro and in vivo studies demonstrated that 20 restored the activity of β-lactam antibiotics against carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Enterobacteriaceae. Taniborbactam is the first pan-spectrum β-lactamase inhibitor to enter clinical development.	Nov 2019
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Structure-guided enhancement of selectivity of chemical probe inhibitors targeting bacterial seryl-tRNA synthetase Ricky Cain , Ramya Salimraj , Avinash Punekar , Dom Belini , Colin W. G. Fishwick , Lloyd Czaplewski , David Jan Scott , Gemma Harris , Christopher G. Dowson , Adrian J. Lloyd , David I. Roper Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b01131 Diamond Proposal Number(s): [14692] Show Abstract ▼ Abstract: Aminoacyl-tRNA synthetases are ubiquitous and essential enzymes for protein synthesis and also a variety of other metabolic processes, especially in bacterial species. Bacterial aminoacyl-tRNA synthetases represent attractive and validated targets for antimicrobial drug discovery if issues of prokaryotic versus eukaryotic selectivity and antibiotic resistance generation can be addressed. We have determined high resolution X-ray crystal structures of the Escherichia coli and Staphylococcus aureus seryl-tRNA synthetases in complex with aminoacyl adenylate analogues and applied a structure-based drug discovery approach to explore and identify a series of small molecule inhibitors that selectively inhibit bacterial seryl-tRNA synthetases with greater than two orders of magnitude compared to their human homologue, demonstrating a route to selective chemical inhibition of these bacterial targets.	Oct 2019
I03-Macromolecular Crystallography	Structure–activity relationships of cyclo(L-tyrosyl-L-tyrosine) derivatives binding to Mycobacterium tuberculosis CYP121: iodinated analogues promote shift to high-spin adduct Sunnia Rajput , Kirsty J. Mclean , Harshwardhan Poddar , Irwin R. Selvam , Gayathri Nagalingam , James A Triccas , Colin W. Levy , Andrew W. Munro , Craig A. Hutton Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b01199 Diamond Proposal Number(s): [8997, 17773] Show Abstract ▼ Abstract: A series of analogues of cyclo(L-tyrosyl-L-tyrosine), the substrate of the Mycobacterium tuberculosis enzyme CYP121, have been synthesized and analyzed by UV-Vis and EPR spectroscopy and by X-ray crystallography. The introduction of iodine substituents onto cyclo(L-tyrosyl-L-tyrosine) results in sub-μM binding affinity for the CYP121 enzyme and a complete shift to the high spin state of the heme FeIII. The introduction of halogens that are able to interact with heme groups is thus a feasible approach to the development of next-generation, tight binding inhibitors of the CYP121 enzyme, in the search for novel anti-tubercular compounds.	Oct 2019
I03-Macromolecular Crystallography	Design, synthesis, and biological evaluation of novel indoles targeting the influenza PB2 cap binding region David Craig Mcgowan , Wendy Balemans , Werner Embrechts , Magali Motte , Jeremy Keown , Christophe Buyck , Jordi Corbera , Mario Funes , Laura Moreno , Ludwig Cooymans , Abdellah Tahri , Julien Eymard , Bart Stoops , Rudy Strijbos , Joke Van Den Berg , Ervin Fodor , Jonathan Grimes , Anil Koul , Tim H. M. Jonckers , Pierre Raboisson , Jerome Guillemont Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b01091 Diamond Proposal Number(s): [14744] Show Abstract ▼ Abstract: In the search for novel influenza inhibitors we evaluated 7-fluoro-substituted indoles as bioisosteric replacements for the 7-azaindole scaffold of Pimodivir, a PB2 (polymerase basic protein 2) inhibitor currently in clinical development. Specifically, a 5,7-difluoroindole derivative 11a was identified as a potent and metabolically stable influenza inhibitor. 11a demonstrated a favorable oral pharmacokinetic profile and in vivo efficacy in mice. In addition, it was found that 11a was not at risk of metabolism via aldehyde oxidase, an advantage over previously described inhibitors of this class. The crystal structure of 11a bound to influenza A PB2 cap region is disclosed here and deposited to the PDB.	Oct 2019
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	A chemical probe for tudor domain protein spindlin1 to investigate chromatin function Vincent Fagan , Catrine Johansson , Carina Gileadi , Octovia Monteiro , James Edward Dunford , Reshma Nibhani , Martin Philpott , Jessica Malzahn , Graham Wells , Ruth Farham , Adam Cribbs , Nadia Halidi , Fengling Li , Irene Chau , Holger Greschik , Srikannathasan Velupillai , Abdellah Allali-hassani , James M. Bennett , Thomas Christott , Charline Giroud , Andrew M. Lewis , Kilian V. M. Huber , Nick Athanasou , Chas Bountra , Manfred Jung , Roland Schüle , Masoud Vedadi , Cheryl H. Arrowsmith , Yan Xiong , Jian Jin , Oleg Fedorov , Gillian Farnie , Paul E. Brennan , Udo C. T. Oppermann Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b00562 Diamond Proposal Number(s): [10619, 15433] Show Abstract ▼ Abstract: Modifications of histone tails, including lysine/arginine methylation, provide the basis of a 'chromatin or histone code'. Proteins that con-tain 'reader' domains can bind to these modifications and form specific effector complexes, which ultimately mediate chromatin function. The spindlin1 (SPIN1) protein contains three Tudor methyl-lysine/arginine reader domains and was identified as a putative onco-gene and transcriptional co-activator. Here we report a SPIN1 chemi-cal probe inhibitor with low nanomolar in vitro activity, exquisite selectivity on a panel of methyl reader and writer proteins, and with submicromolar cellular activity. X-ray crystallography showed that this Tudor domain chemical probe simultaneously engages Tudor domains 1 and 2 via a bidentate binding mode. Small molecule inhibition and siRNA knockdown of SPIN1, as well as chemoproteomic studies, iden-tified genes which are transcriptionally regulated by SPIN1 in squa-mous cell carcinoma and suggest that SPIN1 may have a roll in cancer related inflammation and/or cancer metastasis.	Sep 2019
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Targeting of fumarate hydratase from Mycobacterium tuberculosis using allosteric inhibitors with a dimeric-binding mode Andrew J. Whitehouse , M. Daben J. Libardo , Monica Kasbekar , Paul D. Brear , Gerhard Fischer , Craig J. Thomas , Clifton E. Barry , Helena I. M. Boshoff , Anthony G. Coyne , Chris Abell Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b01203 Diamond Proposal Number(s): [18548] Show Abstract ▼ Abstract: With the growing worldwide prevalence of antibiotic-resistant strains of tuberculosis (TB), new targets are urgently required for the development of treatments with novel modes of action. Fumarate hydratase (fumarase), a vulnerable component of the citric acid cycle in Mycobacterium tuberculosis (Mtb), is a metabolic target that could satisfy this unmet demand. A key challenge in the targeting of Mtb fumarase is its similarity to the human homolog, which shares an identical active site. A potential solution to this selectivity problem was previously found in a high-throughput screening hit that binds in a non-conserved allosteric site. In this work, a structure-activity relationship study was carried out with the determination of further structural biology on the lead series, affording derivatives with sub-micromolar inhibition. Further, the screening of this series against Mtb in vitro identified compounds with potent minimum inhibitory concentrations (MIC).	Sep 2019

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