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168 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
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
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Structure-guided discovery of a selective Mcl-1 inhibitor with cellular activity Zoltan Szlávik , Levente Ondi , Márton Csékei , Attila Paczal , Zoltán B. Szabó , Gábor Radics , James Murray , James Davidson , Ijen Chen , Ben Davis , Roderick E. Hubbard , Christopher Pedder , Pawel Dokurno , Allan Surgenor , Julia Smith , Alan Robertson , Gaetane Letoumelin-braizat , Nicolas Cauquil , Marion Zarka , Didier Demarles , Francoise Perron-sierra , Audrey Claperon , Frederic Colland , Olivier Geneste , András Kotschy Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b00134 Diamond Proposal Number(s): [17182, 1194, 2103] Show Abstract ▼ Abstract: Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation when observed in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy, has emerged as an attractive target for cancer therapy. Here, we report the discovery of selective small molecule inhibitors of Mcl-1 that inhibit cellular activity. Fragment screening identified thienopyrimidine amino acids as promising but nonselective hits that were optimized using nuclear magnetic resonance and X-ray-derived structural information. The introduction of hindered rotation along a biaryl axis has conferred high selectivity to the compounds, and cellular activity was brought on scale by offsetting the negative charge of the anchoring carboxylate group. The obtained compounds described here exhibit nanomolar binding affinity and mechanism-based cellular efficacy, caspase induction, and growth inhibition. These early research efforts illustrate drug discovery optimization from thienopyrimidine hits to a lead compound, the chemical series leading to the identification of our more advanced compounds S63845 and S64315.	Jul 2019
I04-Macromolecular Crystallography	Discovery of a potent and selective fragment-like inhibitor of methyllysine reader protein spindlin 1 (SPIN1) Yan Xiong , Holger Greschik , Catrine Johansson , Ludwig Seifert , Johannes Bacher , Kwang-su Park , Nicolas Babault , Michael L. Martini , Vincent Fagan , Fengling Li , Irene Chau , Thomas Christott , David Dilworth , Dalia Barsyte-lovejoy , Masoud Vedadi , Cheryl H. Arrowsmith , Paul E. Brennan , Oleg Fedorov , Manfred Jung , Gillian Farnie , Jing Liu , Udo C. T. Oppermann , Roland Schüle , Jian Jin Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b00522 Show Abstract ▼ Abstract: By screening an epigenetic compound library, we identified that UNC0638, a highly potent inhibitor of the histone methyltransferases G9a and GLP, was a weak inhibitor of SPIN1 (Spindlin 1), a methyllysine reader protein. Our optimization of this weak hit resulted in the discovery of a potent, selective and cell-active SPIN1 inhibitor, compound 3 (MS31). Compound 3 potently inhibited binding of trimethyllysine-containing peptides to SPIN1, displayed high binding affinity, was highly selective for SPIN1 over other epigenetic readers and writers, directly engaged SPIN1 in cells, and was not toxic to non-tumorigenic cells. The crystal structure of the SPIN1–compound 3 complex indicated that it selectively binds Tudor domain II of SPIN1. We also designed a structurally similar but inactive compound 4 (MS31N) as a negative control. Our results have demonstrated for the first time that potent, selective and cell-active fragment-like inhibitors can be generated by targeting a single Tudor domain.	Jul 2019
I04-Macromolecular Crystallography	2-amino-2, 3-dihydro-1h-indene-5-carboxamide-based discoidin domain receptors 1 (DDR1) inhibitors: design, synthesis, and in vivo anti-pancreatic cancer efficacy Dongsheng Zhu , Huocong Huang , Daniel Pinkas , Jinfeng Luo , Debolina Ganguly , Alice E. Fox , Emily Arner , Qiuping Xiang , Zheng-chao Tu , Alex N. Bullock , Rolf A Brekken , Ke Ding , Xiaoyun Lu Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b00365 Diamond Proposal Number(s): [15433] Show Abstract ▼ Abstract: Pancreatic cancer is a leading cause of cancer-related death. A series of 2-amino-2, 3-dihydro-1H-indene-5-carboxamide derivatives were designed and synthesized as novel selective DDR1 inhibitors to exhibit promising in vitro and in vivo anti-pancreatic cancer activity. One of the representative compounds, 7f, binds with DDR1 with a Kd value of 5.9 nM and suppresses the kinase activity with an IC50 value of 14.9 nM, but is significantly less potent for majority of a panel of 403 wild-type kinases. The compound potently inhibited collagen-induced epithelial-mesenchymal transition (EMT) and dose-dependently suppressed colony formation of pancreatic cancer cells. Furthermore, 7f also demonstrated reasonable pharmacokinetic profiles and displayed promising in vivo therapeutic efficacy in an orthotopic mouse model of pancreatic cancer. Compound 7f may serve as a new lead compound for future drug discovery.	Jul 2019
I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Development of inhibitors against Mycobacterium abscessus tRNA (m 1 G37) methyltransferase (TrmD) using fragment-based approaches Andrew J. Whitehouse , Sherine E. Thomas , Karen P. Brown , Alexander Fanourakis , Daniel S.-h. Chan , M. Daben J. Libardo , Vitor Mendes , Helena I. M. Boshoff , R. Andres Floto , Chris Abell , Tom Blundell , Anthony G. Coyne Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b00809 Diamond Proposal Number(s): [9537, 14043, 18548] Open Access Show Abstract ▼ Abstract: Mycobacterium abscessus (Mab) is a rapidly growing species of multidrug-resistant nontuberculous mycobacteria that has emerged as a growing threat to individuals with cystic fibrosis and other pre-existing chronic lung diseases. Mab pulmonary infections are difficult, or sometimes impossible, to treat and result in accelerated lung function decline and premature death. There is therefore an urgent need to develop novel antibiotics with improved efficacy. tRNA (m1G37) methyltransferase (TrmD) is a promising target for novel antibiotics. It is essential in Mab and other mycobacteria, improving reading frame maintenance on the ribosome to prevent frameshift errors. In this work, a fragment-based approach was employed with the merging of two fragments bound to the active site, followed by structure-guided elaboration to design potent nanomolar inhibitors against Mab TrmD. Several of these compounds exhibit promising activity against mycobacterial species, including Mycobacterium tuberculosis and Mycobacterium leprae in addition to Mab, supporting the use of TrmD as a target for the development of antimycobacterial compounds.	Jul 2019
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Discovery of a first-in-class Receptor Interacting Protein 2 (RIP2) kinase specific clinical candidate, 2-((4-(Benzo[ d ]thiazol-5-ylamino)-6-( tert -butylsulfonyl)quinazolin-7-yl)oxy)ethyl dihydrogen phosphate, for the treatment of inflammatory diseases Pamela A. Haile , Linda N. Casillas , Bartholomew J. Votta , Gren Z. Wang , Adam K. Charnley , Xiaoyang Dong , Michael J. Bury , Joseph J. Romano , John F. Mehlmann , Bryan W. King , Karl F. Erhard , Charles R. Hanning , David B. Lipshutz , Biva M. Desai , Carol A. Capriotti , Michelle C. Schaeffer , Scott B. Berger , Mukesh K. Mahajan , Michael A. Reilly , Rakesh Nagilla , Elizabeth J. Rivera , Helen H. Sun , John K. Kenna , Allison M. Beal , Michael T. Ouellette , Mike Kelly , Gillian Stemp , Máire A. Convery , Anna Vossenkämper , Thomas T. Macdonald , Peter J. Gough , John Bertin , Robert W. Marquis Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b00575 Diamond Proposal Number(s): [1195, 5799] Show Abstract ▼ Abstract: RIP2 kinase has been identified as a key signal transduction partner in the NOD2 pathway contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP2 kinase or its signaling partners on the NOD2 pathway that are suitable for advancement into the clinic have yet to be described. Herein, we report our discovery and profile of the prodrug clinical compound, inhibitor 3, currently in phase 1 clinical studies. Compound 3 potently binds to RIP2 kinase with good kinase specificity and has excellent activity in blocking many proinflammatory cytokine responses in vivo and in human IBD explant samples. The highly favorable physicochemical and ADMET properties of 3 combined with high potency led to a predicted low oral dose in humans.	Jul 2019

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