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181 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-Macromolecular Crystallography	Lead optimization of phthalazinone phosphodiesterase inhibitors as novel antitrypanosomal compounds Irene G. Salado , Abhimanyu Singh , Carlos Moreno-cinos , Guna Sakaine , Marco Siderius , Pieter Van Der Veken , An Matheeussen , Tiffany Van Der Meer , Payman Sadek , Sheraz Gul , Louis Maes , Geert Jan Sterk , Rob Leurs , David Brown , Koen Augustyns Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b00985 Diamond Proposal Number(s): [16207, 15075] Show Abstract ▼ Abstract: Human African trypanosomiasis is causing thousands of deaths every year in the rural areas of Africa. In this manuscript we describe the optimization of a family of phtalazinone derivatives. Phosphodiesterases have emerged as attractive molecular targets for a novel treatment for a variety of neglected parasitic diseases. Compound 1 resulted to be a potent TbrPDEB1 inhibitor with interesting activity against T. brucei in a phenotypic screen. Derivative 1 was studied in an acute in vivo mouse disease model but unfortunately showed no efficacy due to low metabolic stability. We report structural modifications to achieve compounds with an improved metabolic stability while maintaining high potency against TbrPDEB1 and T. brucei. Compound 14, presented a good microsomal stability in mouse and human microsomes and provides a good starting point for future efforts.	Mar 2020
I04-1-Macromolecular Crystallography (fixed wavelength)	The antiepileptic drug carbamazepine binds to a novel pocket on the Wnt receptor Frizzled-8 Yuguang Zhao , Jingshan Ren , James Hillier , Weixian Lu , E. Yvonne Jones Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b02020 Diamond Proposal Number(s): [14744] Show Abstract ▼ Abstract: Misregulation of Wnt signalling is common in human cancer. Development of small molecule inhibitors against the Wnt receptor, Frizzled (FZD), may have potential in cancer therapy. During small molecule screens, we observed binding of carbamazepine (CBZ) to the cysteine-rich domain (CRD) of the Wnt receptor FZD8 using surface plasmon resonance (SPR). Cellular functional assays demonstrated CBZ can suppress FZD8 mediated Wnt/β-catenin signalling. We determined the crystal structure of the complex at 1.7Å resolution, which reveals that CBZ binds at a novel pocket on the FZD8 CRD. The unique residue Tyr52 discriminates FZD8 from the closely-related FZD5 and other FZDs for CBZ binding. The first small molecule-bound FZD structure provides a basis for anti-FZD drug development. Furthermore, the observed CBZ mediated Wnt signalling inhibition may help to explain the phenomenon of bone loss and increased adipogenesis in some patients during long-term CBZ treatment.	Feb 2020
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Structure-based design and pharmacokinetic optimization of covalent allosteric inhibitors of the mutant GTPase KRAS G12C Jason G. Kettle , Sharan K. Bagal , Sue Bickerton , Michael S. Bodnarchuk , Jason Breed , Rodrigo J. Carbajo , Doyle J. Cassar , Atanu Chakraborty , Sabina Cosulich , Iain Cumming , Michael Davies , Andrew Eatherton , Laura Evans , Lyman Feron , Shaun Fillery , Emma Gleave , Frederick W. Goldberg , Stephanie Harlfinger , Lyndsey Hanson , Martin Howard , Rachel Howells , Anne Jackson , Paul Kemmitt , Jennifer K. Kingston , Scott Lamont , Hilary J. Lewis , Songlei Li , Libin Liu , Derek Ogg , Christopher Phillips , Radek Polanski , Graeme Robb , David Robinson , Sarah Ross , James M. Smith , Michael Tonge , Rebecca Whiteley , Junsheng Yang , Longfei Zhang , Xiliang Zhao Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b01720 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an “Achilles heel” and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket on GDP-bound RAS, locking it in an inactive state. A weak inhibitor at this site was optimized through conformational locking of a piperazine–quinazoline motif and linker modification. Subsequent introduction of a key methyl group to the piperazine resulted in enhancements in potency, permeability, clearance, and reactivity, leading to identification of a potent KRASG12C inhibitor with high selectivity and excellent cross-species pharmacokinetic parameters and in vivo efficacy.	Feb 2020
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
I04-1-Macromolecular Crystallography (fixed wavelength)	Structure-bBased design and identification of FT-2102 (olutasidenib), a potent mutant-selective IDH1 inhibitor Justin A. Caravella , Jian Lin , R. Bruce Diebold , Ann-marie Campbell , Anna Ericsson , Gary Gustafson , Zhongguo Wang , Jennifer Castro , Andrea Clarke , Deepali Gotur , Helen R. Josephine , Marie Katz , Mark Kershaw , Lili Yao , Angela V. Toms , Kenneth J. Barr , Christopher J. Dinsmore , Duncan Walker , Susan Ashwell , Wei Lu Journal Of Medicinal Chemistry 63, 1612 - 1623 DOI: 10.1021/acs.jmedchem.9b01423 Show Abstract ▼ Abstract: Inhibition of mutant IDH1 is being evaluated clinically as a treatment option for oncology. Here we describe the structure-based design and optimization of quinoline lead compounds to identify FT-2102, a potent, orally bioavailable, brain penetrant, and selective mIDH1 inhibitor. FT-2102 has excellent ADME/PK properties and reduces 2-hydroxyglutarate levels in an mIDH1 xenograft tumor model. This compound has been selected as a candidate for clinical development in hematologic malignancies, solid tumors, and gliomas with mIDH1.	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

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