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236 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	1,2,4-Triazole-3-thione compounds with a 4-ethyl alkyl/aryl sulfide substituent are broad-spectrum metallo-β-lactamase inhibitors with re-sensitization activity Alice Legru , Federica Verdirosa , Jean-François Hernandez , Giusi Tassone , Filomena Sannio , Manuela Benvenuti , Pierre-Alexis Conde , Guillaume Bossis , Caitlyn A. Thomas , Michael W. Crowder , Melissa Dillenberger , Katja Becker , Cecilia Pozzi , Stefano Mangani , Jean-Denis Docquier , Laurent Gavara European Journal Of Medicinal Chemistry 40 DOI: 10.1016/j.ejmech.2021.113873 Diamond Proposal Number(s): [21741] Show Abstract ▼ Abstract: Metallo-β-lactamases (MBLs) are important contributors of Gram-negative bacteria resistance to β-lactam antibiotics. MBLs are highly worrying because of their carbapenemase activity, their rapid spread in major human opportunistic pathogens while no clinically useful inhibitor is available yet. In this context, we are exploring the potential of compounds based on the 1,2,4-triazole-3-thione scaffold as an original ligand of the di-zinc active sites of MBLs, and diversely substituted at its positions 4 and 5. Here, we present a new series of compounds substituted at the 4-position by a thioether-containing alkyl chain with a carboxylic and/or an aryl group at its extremity. Several compounds showed broad-spectrum inhibition with Ki values in the μM to sub-μM range against VIM-type enzymes, NDM-1 and IMP-1. The presence of the sulfur and of the aryl group was important for the inhibitory activity and the binding mode of a few compounds in VIM-2 was revealed by X-ray crystallography. Importantly, in vitro antibacterial susceptibility assays showed that several inhibitors were able to potentiate the activity of meropenem on Klebsiella pneumoniae clinical isolates producing VIM-1 or VIM-4, with a potentiation effect of up to 16-fold. Finally, a selected compound was found to only moderately inhibit the di-zinc human glyoxalase II, and several showed no or only moderate toxicity toward several human cells, thus favourably completing a promising behaviour.	Oct 2021
I03-Macromolecular Crystallography	Discovery of GSK251: A highly potent, highly selective, orally bioavailable inhibitor of PI3KΔ with a novel binding mode Kenneth Down , Augustin Amour , Niall A. Anderson , Nick Barton , Sebastien Campos , Edward P. Cannons , Cole Clissold , Maire A. Convery , John J. Coward , Kevin Doyle , Birgit Duempelfeld , Christopher D. Edwards , Michael D. Goldsmith , Jana Krause , David N. Mallett , Grant A. Mcgonagle , Vipulkumar K. Patel , James Rowedder , Paul Rowland , Andrew Sharpe , Srividya Sriskantharajah , Daniel A. Thomas , Douglas W. Thomson , Sorif Uddin , J. Nicole Hamblin , Edith M. Hessel Journal Of Medicinal Chemistry 64, 13780 - 13792 DOI: 10.1021/acs.jmedchem.1c01102 Show Abstract ▼ Abstract: Optimization of a previously reported lead series of PI3Kδ inhibitors with a novel binding mode led to the identification of a clinical candidate compound 31 (GSK251). Removal of an embedded Ames-positive heteroaromatic amine by reversing a sulfonamide followed by locating an interaction with Trp760 led to a highly selective compound 9. Further optimization to avoid glutathione trapping, to enhance potency and selectivity, and to optimize an oral pharmacokinetic profile led to the discovery of compound 31 (GSK215) that had a low predicted daily dose (45 mg, b.i.d) and a rat toxicity profile suitable for further development.	Sep 2021
I03-Macromolecular Crystallography	Optimization of an imidazo[1,2-a]pyridine series to afford highly selective type i1/2 dual Mer/Axl kinase inhibitors with in vivo efficacy William Mccoull , Scott Boyd , Martin R. Brown , Muireann Coen , Olga Collingwood , Nichola L. Davies , Ann Doherty , Gary Fairley , Kristin Goldberg , Elizabeth Hardaker , Guang He , Edward J. Hennessy , Philip Hopcroft , George Hodgson , Anne Jackson , Xiefeng Jiang , Ankur Karmokar , Anne-Laure Lainé , Nicola Lindsay , Yumeng Mao , Roshini Markandu , Lindsay Mcmurray , Neville Mclean , Lorraine Mooney , Helen Musgrove , J. Willem M. Nissink , Alexander Pflug , Venkatesh Pilla Reddy , Philip B. Rawlins , Emma Rivers , Marianne Schimpl , Graham F. Smith , Sharon Tentarelli , Jon Travers , Robert I. Troup , Josephine Walton , Cheng Wang , Stephen Wilkinson , Beth Williamson , Jon Winter-Holt , Dejian Yang , Yuting Zheng , Qianxiu Zhu , Paul D. Smith Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c00920 Diamond Proposal Number(s): [17180] Show Abstract ▼ Abstract: Inhibition of Mer and Axl kinases has been implicated as a potential way to improve the efficacy of current immuno-oncology therapeutics by restoring the innate immune response in the tumor microenvironment. Highly selective dual Mer/Axl kinase inhibitors are required to validate this hypothesis. Starting from hits from a DNA-encoded library screen, we optimized an imidazo[1,2-a]pyridine series using structure-based compound design to improve potency and reduce lipophilicity, resulting in a highly selective in vivo probe compound 32. We demonstrated dose-dependent in vivo efficacy and target engagement in Mer- and Axl-dependent efficacy models using two structurally differentiated and selective dual Mer/Axl inhibitors. Additionally, in vivo efficacy was observed in a preclinical MC38 immuno-oncology model in combination with anti-PD1 antibodies and ionizing radiation.	Sep 2021
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	Discovery of novel UDP-N-acetylglucosamine acyltransferase (LpxA) inhibitors with activity against pseudomonas aeruginosa M. Dominic Ryan , Alastair L. Parkes , David Corbett , Anthony P. Dickie , Michelle Southey , Ole A. Andersen , Daniel B. Stein , Olivier R. Barbeau , Angelo Sanzone , Pia Thommes , John Barker , Ricky Cain , Christel Compper , Magali Dejob , Alain Dorali , Donnya Etheridge , Sian Evans , Adele Faulkner , Elise Gadouleau , Timothy Gorman , Denes Haase , Maisie Holbrow-Wilshaw , Thomas Krulle , Xianfu Li , Christopher Lumley , Barbara Mertins , Spencer Napier , Rajesh Odedra , Kostas Papadopoulos , Vasileios Roumpelakis , Kate Spear , Emily Trimby , Jennifer Williams , Michael Zahn , Anthony D. Keefe , Ying Zhang , Holly T. Soutter , Paolo A. Centrella , Matthew A. Clark , John W. Cuozzo , Christoph E. Dumelin , Boer Deng , Avery Hunt , Eric A. Sigel , Dawn M. Troast , Boudewijn L. M. Dejonge Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c00888 Diamond Proposal Number(s): [20021, 23279] Show Abstract ▼ Abstract: This study describes a novel series of UDP-N-acetylglucosamine acyltransferase (LpxA) inhibitors that was identified through affinity-mediated selection from a DNA-encoded compound library. The original hit was a selective inhibitor of Pseudomonas aeruginosa LpxA with no activity against Escherichia coli LpxA. The biochemical potency of the series was optimized through an X-ray crystallography-supported medicinal chemistry program, resulting in compounds with nanomolar activity against P. aeruginosa LpxA (best half-maximal inhibitory concentration (IC50) <5 nM) and cellular activity against P. aeruginosa (best minimal inhibitory concentration (MIC) of 4 μg/mL). Lack of activity against E. coli was maintained (IC50 > 20 μM and MIC > 128 μg/mL). The mode of action of analogues was confirmed through genetic analyses. As expected, compounds were active against multidrug-resistant isolates. Further optimization of pharmacokinetics is needed before efficacy studies in mouse infection models can be attempted. To our knowledge, this is the first reported LpxA inhibitor series with selective activity against P. aeruginosa.	Sep 2021
I04-1-Macromolecular Crystallography (fixed wavelength)	Discovery of a potent dual SLK/STK10 inhibitor based on a maleimide scaffold Ricardo A. M. Serafim , Fiona J. Sorrell , Benedict-Tilman Berger , Ross J. Collins , Stanley N. S. Vasconcelos , Katlin B. Massirer , Stefan Knapp , James Bennett , Oleg Fedorov , Hitesh Patel , William J. Zuercher , Jonathan M. Elkins Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c01579 Diamond Proposal Number(s): [15433] Show Abstract ▼ Abstract: SLK (STE20-like kinase) and STK10 (serine/threonine kinase 10) are closely related kinases whose enzymatic activity is linked to the regulation of ezrin, radixin, and moesin function and to the regulation of lymphocyte migration and the cell cycle. We identified a series of 3-anilino-4-arylmaleimides as dual inhibitors of SLK and STK10 with good kinome-wide selectivity. Optimization of this series led to multiple SLK/STK10 inhibitors with nanomolar potency. Crystal structures of exemplar inhibitors bound to SLK and STK10 demonstrated the binding mode of the inhibitors and rationalized their selectivity. Cellular target engagement assays demonstrated the binding of the inhibitors to SLK and STK10 in cells. Further selectivity analyses, including analysis of activity of the reported inhibitors against off-targets in cells, identified compound 31 as the most potent and selective inhibitor of SLK and STK10 yet reported.	Aug 2021
I02-Macromolecular Crystallography I03-Macromolecular Crystallography	Discovery of a highly selective BET BD2 inhibitor from a DNA-encoded library technology screening hit Francesco Rianjongdee , Stephen J. Atkinson , Chun-Wa Chung , Paola Grandi , James R. J. Gray , Laura J. Kaushansky , Patricia Medeiros , Cassie Messenger , Alex Phillipou , Alex Preston , Rab K. Prinjha , Inmaculada Rioja , Alexander L. Satz , Simon Taylor , Ian D. Wall , Robert J. Watson , Gang Yao , Emmanuel H. Demont Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c00412 Show Abstract ▼ Abstract: Second-generation bromodomain and extra terminal (BET) inhibitors, which selectively target one of the two bromodomains in the BET proteins, have begun to emerge in the literature. These inhibitors aim to help determine the roles and functions of each domain and assess whether they can demonstrate an improved safety profile in clinical settings compared to pan-BET inhibitors. Herein, we describe the discovery of a novel BET BD2-selective chemotype using a structure-based drug design from a hit identified by DNA-encoded library technologies, showing a structural differentiation from key previously reported greater than 100-fold BD2-selective chemotypes GSK620, GSK046, and ABBV-744. Following a structure-based hypothesis for the selectivity and optimization of the physicochemical properties of the series, we identified 60 (GSK040), an in vitro ready and in vivo capable BET BD2-inhibitor of unprecedented selectivity (5000-fold) against BET BD1, excellent selectivity against other bromodomains, and good physicochemical properties. This novel chemical probe can be added to the toolbox used in the advancement of epigenetics research.	Jul 2021
I03-Macromolecular Crystallography	Hinge binder scaffold hopping identifies potent calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) inhibitor chemotypes Benjamin J. Eduful , Sean N. O'Byrne , Louisa Temme , Christopher R. M. Asquith , Yi Liang , Alfredo Picado , Joseph R. Pilotte , Mohammad Anwar Hossain , Carrow I. Wells , William J. Zuercher , Carolina M. C. Catta-Preta , Priscila Zonzini Ramos , André De S. Santiago , Rafael M. Counago , Christopher G. Langendorf , Kévin Nay , Jonathan S. Oakhill , Thomas L. Pulliam , Chenchu Lin , Dominik Awad , Timothy M. Willson , Daniel E. Frigo , John W. Scott , David H. Drewry Journal Of Medicinal Chemistry 8 DOI: 10.1021/acs.jmedchem.0c02274 Diamond Proposal Number(s): [10619] Open Access Show Abstract ▼ Abstract: CAMKK2 is a serine/threonine kinase and an activator of AMPK whose dysregulation is linked with multiple diseases. Unfortunately, STO-609, the tool inhibitor commonly used to probe CAMKK2 signaling, has limitations. To identify promising scaffolds as starting points for the development of high-quality CAMKK2 chemical probes, we utilized a hinge-binding scaffold hopping strategy to design new CAMKK2 inhibitors. Starting from the potent but promiscuous disubstituted 7-azaindole GSK650934, a total of 32 compounds, composed of single-ring, 5,6-, and 6,6-fused heteroaromatic cores, were synthesized. The compound set was specifically designed to probe interactions with the kinase hinge-binding residues. Compared to GSK650394 and STO-609, 13 compounds displayed similar or better CAMKK2 inhibitory potency in vitro, while compounds 13g and 45 had improved selectivity for CAMKK2 across the kinome. Our systematic survey of hinge-binding chemotypes identified several potent and selective inhibitors of CAMKK2 to serve as starting points for medicinal chemistry programs.	Jul 2021
I02-Macromolecular Crystallography I03-Macromolecular Crystallography	Identification of a series of n-methylpyridine-2-carboxamides as potent and selective inhibitors of the second bromodomain (BD2) of the bromo and extra terminal domain (BET) proteins Lee A. Harrison , Stephen J. Atkinson , Anna Bassil , Chun-Wa Chung , Paola Grandi , James R. J. Gray , Etienne Levernier , Antonia Lewis , David Lugo , Cassie Messenger , Anne-Marie Michon , Darren J. Mitchell , Alex Preston , Rab K. Prinjha , Inmaculada Rioja , Jonathan T. Seal , Simon Taylor , Ian D. Wall , Robert J. Watson , James M. Woolven , Emmanuel H. Demont Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c02155 Show Abstract ▼ Abstract: Domain-specific BET bromodomain ligands represent an attractive target for drug discovery with the potential to unlock the therapeutic benefits of antagonizing these proteins without eliciting the toxicological aspects seen with pan-BET inhibitors. While we have reported several distinct classes of BD2 selective compounds, namely, GSK620, GSK549, and GSK046, only GSK046 shows high aqueous solubility. Herein, we describe the lead optimization of a further class of highly soluble compounds based upon a picolinamide chemotype. Focusing on achieving >1000-fold selectivity for BD2 over BD1 ,while retaining favorable physical chemical properties, compound 36 was identified as being 2000-fold selective for BD2 over BD1 (Brd4 data) with >1 mg/mL solubility in FaSSIF media. 36 represents a valuable new in vivo ready molecule for the exploration of the BD2 phenotype.	Jul 2021
I02-Macromolecular Crystallography	Optimization of a series of 2,3-dihydrobenzofurans as highly potent, second bromodomain (BD2)-selective, bromo and extra-terminal domain (BET) inhibitors Simon C. C. Lucas , Stephen J. Atkinson , Chun-Wa Chung , Rob Davis , Laurie Gordon , Paola Grandi , James J. R. Gray , Thomas Grimes , Alexander Phillipou , Alex G. Preston , Rab K. Prinjha , Inmaculada Rioja , Simon Taylor , Nicholas C. O. Tomkinson , Ian Wall , Robert J. Watson , James Woolven , Emmanuel H. Demont Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c00344 Show Abstract ▼ Abstract: Herein, a series of 2,3-dihydrobenzofurans have been developed as highly potent bromo and extra-terminal domain (BET) inhibitors with 1000-fold selectivity for the second bromodomain (BD2) over the first bromodomain (BD1). Investment in the development of two orthogonal synthetic routes delivered inhibitors that were potent and selective but had raised in vitro clearance and suboptimal solubility. Insertion of a quaternary center into the 2,3-dihydrobenzofuran core blocked a key site of metabolism and improved the solubility. This led to the development of inhibitor 71 (GSK852): a potent, 1000-fold-selective, highly soluble compound with good in vivo rat and dog pharmacokinetics.	Jul 2021

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