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173 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
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
	A qualified success: discovery of a new series of ATAD2 bromodomain inhibitors with a novel binding mode using high-throughput screening and hit qualification Paul Bamborough , Chun-wa Chung , Emmanuel H. Demont , Angela M. Bridges , Peter D. Craggs , David P. Dixon , Peter Francis , Rebecca C. Furze , Paola Grandi , Emma J. Jones , Bhumika Karamshi , Kelly Locke , Simon C. C. Lucas , Anne-marie Michon , Darren J. Mitchell , Peter Pogány , Rab K. Prinjha , Christina Rau , Ana Maria Roa , Andrew D. Roberts , Robert J. Sheppard , Robert J. Watson Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b00673 Show Abstract ▼ Abstract: The bromodomain of ATAD2 has proved to be one of the least-tractable proteins within this target class. Here, we describe the discovery of a new class of inhibitors by high-throughput screening and show how the difficulties encountered in establishing a screening triage capable of finding progressible hits were overcome by data-driven optimization. Despite the prevalence of nonspecific hits and an exceptionally low progressible hit rate (0.001%), our optimized hit qualification strategy employing orthogonal biophysical methods enabled us to identify a single active series. The compounds have a novel ATAD2 binding mode with noncanonical features including the displacement of all conserved water molecules within the active site and a halogen-bonding interaction. In addition to reporting this new series and preliminary structure–activity relationship, we demonstrate the value of diversity screening to complement the knowledge-based approach used in our previous ATAD2 work. We also exemplify tactics that can increase the chance of success when seeking new chemical starting points for novel and less-tractable targets.	Aug 2019
I02-Macromolecular Crystallography	Discovery of first in vivo active inhibitors of soluble epoxide hydrolase (sEH) phosphatase domain Jan S. Kramer , Stefano Woltersdorf , Thomas Duflot , Kerstin Hiesinger , Felix F. Lillich , Felix Knöll , Sandra K. Wittmann , Franca M. Klingler , Steffen Brunst , Apirat Chaikuad , Christophe Morisseau , Bruce D. Hammock , Carola Buccellati , Angelo Sala , G. Enrico Rovati , Matthieu Leuillier , Sylvain Fraineau , Julie Rondeaux , Victor Hernandez Olmos , Jan Heering , Daniel Merk , Denys Pogoryelov , Dieter Steinhilber , Stefan Knapp , Jeremy Bellien , Ewgenij Proschak Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b00445 Show Abstract ▼ Abstract: The emerging pharmacological target soluble epoxide hydrolase (sEH) is a bifunctional enzyme exhibiting two different catalytic activities, which are located in two distinct domains. Although the physiological role of the C-terminal hydrolase domain is well-investigated, little is known about its phosphatase activity located in the N-terminal domain of the sEH (sEH-P). Herein, we report the discovery and optimization of the first inhibitor of human and rat sEH-P, applicable in vivo. X-ray structure analysis of the sEH phosphatase domain complexed with an inhibitor provides insights in the molecular basis of small-molecule sEH-P inhibition and helps to rationalize the structure-activity relationships. 4-(4-(3,4-Dichlorophenyl)-5-phenyloxazol-2-yl)butanoic acid (22b, SWE101) has an excellent pharmacokinetic and pharmacodynamic profile in rats and enables the investigation of the physiological and pathophysiological role of sEH-P in vivo.	Aug 2019
I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Bicyclic boronate VNRX-5133 inhibits metallo- and serine-β-lactamases Alen Krajnc , Jurgen Brem , Philip Hinchliffe , Karina Calvopina , Tharindi Panduwawala , Pauline A. Lang , Jos J. A. G. Kamps , Jonathan M. Tyrell , Emma Widlake , Benjamin G. Saward , Timothy R. Walsh , James Spencer , Christopher J. Schofield Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b00911 Diamond Proposal Number(s): [17212, 18069] Show Abstract ▼ Abstract: The bicyclic boronate VNRX-5133 is a new type of β-lactamase inhibitor in clinical development. We report that VNRX-5133 inhibits serine-β-lactamases (SBLs) and some clinically important metallo-β-lactamases (MBLs), including NDM-1 and VIM-1/2. VNRX-5133 activity against IMP-1 and tested B2/B3 MBLs was lower/not observed. Crystallography reveals how VNRX-5133 binds to the class D SBL OXA-10 and NDM-1. The crystallographic results highlight the ability of bicyclic boronates to inhibit SBLs and MBLs via binding of a tetrahedral (sp3) boron species. The structures imply conserved binding of the bicyclic core with SBLs/MBLs. With NDM-1, by crystallography we observed an unanticipated VNRX-5133 binding mode involving cyclization of its acylamino oxygen onto the boron of the bicyclic core. Different side-chain-dependent binding modes for bicyclic boronates imply scope for optimisation. The results further support the ‘high energy intermediate’ analogue approach for broad-spectrum β-lactamase inhibitor development and highlight the ability of boron-inhibitors to interchange between different hybridization states / binding modes.	Aug 2019

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