Search Results

You searched for all publications:

with publication states 'Published (Approved)'
published in journal 'Journal Of Medicinal Chemistry'

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

213 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 I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Faropenem reacts with serine and metallo-β-lactamases to give multiple products Anka Lucic , Philip Hinchliffe , Tika R. Malla , Catherine L. Tooke , Jurgen Brem , Karina Calvopina , Christopher T. Lohans , Patrick Rabe , Michael A. Mcdonough , Timothy Armistead , Allen M. Orville , James Spencer , Christopher J. Schofield European Journal Of Medicinal Chemistry 6 DOI: 10.1016/j.ejmech.2021.113257 Diamond Proposal Number(s): [17212, 23269, 18069] Open Access Show Abstract ▼ Abstract: Penems have demonstrated potential as antibacterials and β-lactamase inhibitors; however, their clinical use has been limited, especially in comparison with the structurally related carbapenems. Faropenem is an orally active antibiotic with a C2 tetrahydrofuran (THF) ring, which is resistant to hydrolysis by some β-lactamases. We report studies on the reactions of faropenem with carbapenem-hydrolysing β-lactamases, focusing on the class A serine β-lactamase KPC-2 and the metallo β-lactamases (MBLs) VIM-2 (a subclass B1 MBL) and L1 (a B3 MBL). Kinetic studies show that faropenem is a substrate for all three β-lactamases, though it is less efficiently hydrolysed by KPC-2. Crystallographic analyses on faropenem-derived complexes reveal the opening of the β-lactam ring with formation of an imine with KPC-2, VIM-2, and L1. In the cases of the KPC-2 and VIM-2 structures, the THF ring is opened to give an alkene, but with L1 the THF ring remains intact. Solution state studies, employing NMR, were performed on L1, KPC-2, VIM-2, VIM-1, NDM-1, OXA-23, OXA-10, and OXA-48. The solution results reveal, in all cases, formation of imine products in which the THF ring is opened; formation of a THF ring-closed imine product was only observed with VIM-1 and VIM-2. An enamine product with a closed THF ring was also observed in all cases, at varying levels. Combined with previous reports, the results exemplify the potential for different outcomes in the reactions of penems with MBLs and SBLs and imply further structure-activity relationship studies are worthwhile to optimise the interactions of penems with β-lactamases. They also exemplify how crystal structures of β-lactamase substrate/inhibitor complexes do not always reflect reaction outcomes in solution.	Feb 2021
I04-Macromolecular Crystallography	Discovery of ant3310, a novel broad-spectrum serine β-lactamase inhibitor of the diazabicyclooctane class, which strongly potentiates meropenem activity against carbapenem-resistant enterobacterales and Acinetobacter baumannii David T. Davies , Simon Leiris , Magdalena Zalacain , Nicolas Sprynski , Jérôme Castandet , Justine Bousquet , Clarisse Lozano , Agustina Llanos , Laethitia Alibaud , Srinivas Vasa , Ramesh Pattipati , Ravindar Valige , Bhaskar Kummari , Srinivasu Pothukanuri , Cyntia De Piano , Ian Morrissey , Kirsty Holden , Peter Warn , Francesca Marcoccia , Manuela Benvenuti , Cecilia Pozzi , Giusy Tassone , Stefano Mangani , Jean-denis Docquier , David Pallin , Richard Elliot , Marc Lemonnier , Martin Everett Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c01535 Diamond Proposal Number(s): [21741] Show Abstract ▼ Abstract: The diazabicyclooctanes (DBOs) are a class of serine β-lactamase (SBL) inhibitors that use a strained urea moiety as the warhead to react with the active serine residue in the active site of SBLs. The first in-class drug, avibactam, as well as several other recently approved DBOs (e.g., relebactam) or those in clinical development (e.g., nacubactam and zidebactam) potentiate activity of β-lactam antibiotics, to various extents, against carbapenem-resistant Enterobacterales (CRE) carrying class A, C, and D SBLs; however, none of these are able to rescue the activity of β-lactam antibiotics against carbapenem-resistant Acinetobacter baumannii (CRAB), a WHO “critical priority pathogen” producing class D OXA-type SBLs. Herein, we describe the chemical optimization and resulting structure–activity relationship, leading to the discovery of a novel DBO, ANT3310, which uniquely has a fluorine atom replacing the carboxamide and stands apart from the current DBOs in restoring carbapenem activity against OXA-CRAB as well as SBL-carrying CRE pathogens.	Dec 2020
I03-Macromolecular Crystallography	Selective targeting of the αC and DFG-out pocket in p38 MAPK Sandra Röhm , Martin Schroeder , Jessica E. Dwyer , Caroline S. Widdowson , Apirat Chaikuad , Benedict-tilman Berger , Andreas C. Joerger , Andreas Krämer , Jule Harbig , Daniel Dauch , Mark Kudolo , Stefan Laufer , Mark C. Bagley , Stefan Knapp European Journal Of Medicinal Chemistry 208 DOI: 10.1016/j.ejmech.2020.112721 Diamond Proposal Number(s): [10619] Show Abstract ▼ Abstract: The p38 MAPK cascade is a key signaling pathway linked to a multitude of physiological functions and of central importance in inflammatory and autoimmune diseases. Although studied extensively, little is known about how conformation-specific inhibitors alter signaling outcomes. Here, we have explored the highly dynamic back pocket of p38 MAPK with allosteric urea fragments. However, screening against known off-targets showed that these fragments maintained the selectivity issues of their parent compound BIRB-796, while combination with the hinge-binding motif of VPC-00628 greatly enhanced inhibitor selectivity. Further efforts focused therefore on the exploration of the αC-out pocket of p38 MAPK, yielding compound 137 as a highly selective type-II inhibitor. Even though 137 is structurally related to a recent p38 type-II chemical probe, SR-318, the data presented here provide valuable insights into back-pocket interactions that are not addressed in SR-318 and it provides an alternative chemical tool with good cellular activity targeting also the p38 back pocket.	Dec 2020
I02-Macromolecular Crystallography	Structure-based drug design and synthesis of PI3Kα-selective inhibitor (PF-06843195) Hengmiao Cheng , Suvi T. M. Orr , Simon Bailey , Alexei Brooun , Ping Chen , Judith G. Deal , Yali L. Deng , Martin P. Edwards , Gary M. Gallego , Neil Grodsky , Buwen Huang , Mehran Jalaie , Stephen Kaiser , Robert S. Kania , Susan E. Kephart , Jennifer Lafontaine , Martha A. Ornelas , Mason Pairish , Simon Planken , Hong Shen , Scott Sutton , Luke Zehnder , Chau D. Almaden , Shubha Bagrodia , Matthew D. Falk , Hovhannes J. Gukasyan , Caroline Ho , Xiaolin Kang , Rachel E. Kosa , Ling Liu , Mary E. Spilker , Sergei Timofeevski , Ravi Visswanathan , Zhenxiong Wang , Fanxiu Meng , Shijian Ren , Li Shao , Feng Xu , John C. Kath Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c01652 Show Abstract ▼ Abstract: The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is a frequently dysregulated pathway in human cancer, and PI3Kα is one of the most frequently mutated kinases in human cancer. A PI3Kα-selective inhibitor may provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family. Here, we describe our efforts to discover a PI3Kα-selective inhibitor by applying structure-based drug design (SBDD) and computational analysis. A novel series of compounds, exemplified by 2,2-difluoroethyl (3S)-3-{[2′-amino-5-fluoro-2-(morpholin-4-yl)-4,5′-bipyrimidin-6-yl]amino}-3-(hydroxymethyl)pyrrolidine-1-carboxylate (1) (PF-06843195), with high PI3Kα potency and unique PI3K isoform and mTOR selectivity were discovered. We describe here the details of the design and synthesis program that lead to the discovery of 1.	Dec 2020
I04-1-Macromolecular Crystallography (fixed wavelength)	Synthesis, biological evaluation, in silico modeling and crystallization of novel small monocationic molecules with potent antiproliferative activity by dual mechanism Lucía Serran Aguilera , Elena Mariotto , Gianluca Rubbini , Francisco Fermín Castro Navas , Carmen Marco , María Paz Carrasco-jiménez , Marco Ballarotto , Antonio Macchiarulo , Ramon Hurtado-guerrero , Giampietro Viola , Luisa Carlota Lopez-cara European Journal Of Medicinal Chemistry 207 DOI: 10.1016/j.ejmech.2020.112797 Diamond Proposal Number(s): [8035] Show Abstract ▼ Abstract: Seeking for new anticancer drugs with strong antiproliferative activity and simple molecular structure, we designed a novel series of compounds based on our previous reported pharmacophore model composed of five moieties. Antiproliferative assays on four tumoral cell lines and evaluation of Human Choline Kinase CKα1 enzymatic activity was performed for these compounds. Among tested molecules, those ones with biphenyl spacer showed betters enzymatic and antiproliferative activities (n-v). Docking and crystallization studies validate the hypothesis and confirm the results. The most active compound (t) induces a significant arrest of the cell cycle in G0/G1 phase that ultimately lead to apoptosis, following the mitochondrial pathway, as demonstrated for other choline kinase inhibitors. However additional assays reveal that the inhibition of choline uptake could also be involved in the antiproliferative outcome of this class of compounds.	Dec 2020
I02-Macromolecular Crystallography	A chemical probe for dark kinase Stk17b derives its potency and high selectivity through a unique P-Loop conformation Alfredo Picado , Apirat Chaikuad , Carrow I. Wells , Safal Shrestha , William J. Zuercher , Julie E. Pickett , Frank E. Kwarcinski , Parvathi Sinha , Chandi S. De Silva , Reena Zutshi , Shubin Liu , Natarajan Kannan , Stefan Knapp , David H. Drewry , Timothy M. Willson Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c01174 Diamond Proposal Number(s): [442] Show Abstract ▼ Abstract: STK17B is a member of the death-associated protein kinase family and has been genetically linked to the development of diverse diseases. However, the role of STK17B in normal and disease pathology is poorly defined. Here, we present the discovery of thieno[3,2-d] pyrimidine SGC-STK17B-1 (11s), a high-quality chemical probe for this understudied “dark” kinase. 11s is an ATP-competitive inhibitor that showed remarkable selectivity over other kinases including the closely related STK17A. X-ray crystallography of 11s and related thieno[3,2-d]pyrimidines bound to STK17B revealed a unique P-loop conformation characterized by a salt bridge between R41 and the carboxylic acid of the inhibitor. Molecular dynamic simulations of STK17B revealed the flexibility of the P-loop and a wide range of R41 conformations available to the apo-protein. The isomeric thieno[2,3-d]pyrimidine SGC-STK17B-1N (19g) was identified as a negative control compound. The >100-fold lower activity of 19g on STK17B was attributed to the reduced basicity of its pyrimidine N1.	Nov 2020
I02-Macromolecular Crystallography I04-Macromolecular Crystallography	Fragment-based discovery of novel non-hydroxamate LpxC inhibitors with antibacterial activity Yousuke Yamada , Hajime Takashima , David Lee Walmsley , Fumihito Ushiyama , Yohei Matsuda , Harumi Kanazawa , Toru Yamaguchi-sasaki , Nozomi Tanaka-yamamoto , Junya Yamagishi , Risa Kurimoto-tsuruta , Yuya Ogata , Norikazu Ohtake , Hayley Angove , Lisa Baker , Richard Harris , Alba Macias , Alan Robertson , Allan Surgenor , Hayato Watanabe , Koichiro Nakano , Masashi Mima , Kunihiko Iwamoto , Atsushi Okada , Iichiro Takata , Kosuke Hitaka , Akihiro Tanaka , Kiyoko Fujita , Hiroyuki Sugiyama , Roderick E. Hubbard Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c01215 Diamond Proposal Number(s): [12428] Show Abstract ▼ Abstract: UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is a zinc metalloenzyme that catalyzes the first committed step in the biosynthesis of Lipid A, an essential component of the cell envelope of Gram-negative bacteria. The most advanced, disclosed LpxC inhibitors showing antibacterial activity coordinate zinc through a hydroxamate moiety with concerns about binding to other metalloenzymes. Here, we describe the discovery, optimization, and efficacy of two series of compounds derived from fragments with differing modes of zinc chelation. A series was evolved from a fragment where a glycine moiety complexes zinc, which achieved low nanomolar potency in an enzyme functional assay but poor antibacterial activity on cell cultures. A second series was based on a fragment that chelated zinc through an imidazole moiety. Structure-guided design led to a 2-(1S-hydroxyethyl)-imidazole derivative exhibiting low nanomolar inhibition of LpxC and a minimum inhibitory concentration (MIC) of 4 μg/mL against Pseudomonas aeruginosa, which is little affected by the presence of albumin.	Nov 2020
I02-Macromolecular Crystallography	Discovery of S64315, a potent and selective Mcl-1 inhibitor Zoltan Szlavik , Marton Csekei , Attila Paczal , Zoltan B. Szabo , Szabolcs Sipos , Gabor Radics , Agnes Proszenyak , Balazs Balint , James Murray , James Davidson , Ijen Chen , Pawel Dokurno , Allan E Surgenor , Zoe Marie Daniels , Roderick E. Hubbard , Gaëtane Le Toumelin-braizat , Audrey Claperon , Gaëlle Lysiak-auvity , Anne-marie Girard , Alain Bruno , Maia Chanrion , Frédéric Colland , Ana-leticia Maragno , Didier Demarles , Olivier Geneste , Andras Kotschy Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c01234 Diamond Proposal Number(s): [2103] Show Abstract ▼ Abstract: Myeloid cell leukemia 1 (Mcl-1) has emerged as an attractive target for cancer therapy. It is an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here we report the discovery of our clinical candidate S64315, a selective small molecule inhibitor of Mcl-1. Starting from a fragment derived lead compound, we have conducted structure guided optimization that has led to a significant (3 log) improvement of target affinity as well as cellular potency. The presence of hindered rotation along a biaryl axis has conferred high selectivity to the compounds against other members of the Bcl-2 family. During optimization, we have also established predictive PD markers of Mcl-1 inhibition and achieved both efficient in vitro cell killing and tumor regression in Mcl-1 dependent cancer models. The preclinical candidate has drug-like properties that have enabled its development and entry into clinical trials.	Nov 2020
I04-1-Macromolecular Crystallography (fixed wavelength)	Diazaspirononane nonsaccharide inhibitors of O-GlcNAcase (OGA) for the treatment of neurodegenerative disorders Carlos M. Martínez-viturro , Andrés A. Trabanco , Jordi Royes , Elena Fernández , Gary Tresadern , Juan A. Vega , Alcira Del Cerro , Francisca Delgado , Aránzazu García Molina , Fulgencio Tovar , Paul Shaffer , Andreas Ebneth , Alexis Bretteville , Liesbeth Mertens , Marijke Somers , Jose M. Alonso , José M. Bartolomé-nebreda Journal Of Medicinal Chemistry 63, 14017 - 14044 DOI: 10.1021/acs.jmedchem.0c01479 Diamond Proposal Number(s): [16725] Show Abstract ▼ Abstract: O-GlcNAcylation is a post-translational modification of tau understood to lower the speed and yield of its aggregation, a pathological hallmark of Alzheimer’s disease (AD). O-GlcNAcase (OGA) is the only enzyme that removes O-linked N-acetyl-d-glucosamine (O-GlcNAc) from target proteins. Therefore, inhibition of OGA represents a potential approach for the treatment of AD by preserving the O-GlcNAcylated tau protein. Herein, we report the multifactorial optimization of high-throughput screening hit 8 to a potent, metabolically stable, and orally bioavailable diazaspirononane OGA inhibitor (+)-56. The human OGA X-ray crystal structure has been recently solved, but bacterial hydrolases are still widely used as structural homologues. For the first time, we reveal how a nonsaccharide series of inhibitors binds bacterial OGA and discuss the suitability of two different bacterial orthologues as surrogates for human OGA. These breakthroughs enabled structure–activity relationships to be understood and provided context and boundaries for the optimization of druglike properties.	Nov 2020
I02-Macromolecular Crystallography	[1,2,4]triazolo[1,5-a]pyrimidine phosphodiesterase 2A inhibitors: structure and free-energy perturbation-guided exploration Gary Tresadern , Ingrid Velter , Andrés A. Trabanco , Frans Van Den Keybus , Gregor J. Macdonald , Marijke V. F. Somers , Greet Vanhoof , Philip M. Leonard , Marieke B. A. C. Lamers , Yves E. M. Van Roosbroeck , Peter J. J. A. Buijnsters Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c01272 Diamond Proposal Number(s): [5603] Show Abstract ▼ Abstract: We describe the hit-to-lead exploration of a [1,2,4]triazolo[1,5-a]pyrimidine phosphodiesterase 2A (PDE2A) inhibitor arising from high-throughput screening. X-ray crystallography enabled structure-guided design, leading to the identification of preferred substructural components. Further rounds of optimization used relative binding free-energy calculations to prioritize different substituents from the large accessible chemical space. The free-energy perturbation (FEP) calculations were performed for 265 putative PDE2A inhibitors, and 100 compounds were synthesized representing a relatively large prospective application providing unexpectedly active molecules with IC50′s from 2340 to 0.89 nM. Lead compound 46 originating from the FEP calculations showed PDE2A inhibition IC50 of 1.3 ± 0.39 nM, ∼100-fold selectivity versus other PDE enzymes, clean cytochrome P450 profile, in vivo target occupancy, and promise for further lead optimization.	Oct 2020

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