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13 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I04-1-Macromolecular Crystallography (fixed wavelength)	Design and development of lysyl tRNA synthetase inhibitors, for the treatment of tuberculosis Susan H. Davis , Michael Mathieson , Kirsteen I. Buchanan , Alice Dawson , Alasdair Smith , Mattia Cocco , Fabio K. Tamaki , John M. Post , Beatriz Baragaña , Chimed Jansen , Michael Kiczun , Fabio Zuccotto , Gavin Wood , Paul Scullion , Peter C. Ray , Ola Epemolu , Eva Maria Lopez-Román , Laura Guijarro López , Curtis A. Engelhart , Jia Kim , Paula A. Pino , Dirk Schnappinger , Kevin D. Read , Lourdes Encinas , Robert H. Bates , Paul G. Wyatt , Simon R. Green , Laura A. T. Cleghorn Journal Of Medicinal Chemistry 15 DOI: 10.1021/acs.jmedchem.5c01331 Diamond Proposal Number(s): [19844] Open Access Show Abstract ▼ Abstract: There is currently a public health crisis due to the rise of multidrug-resistant tuberculosis cases, as well as the rise in the number of deaths from tuberculosis. To achieve the United Nations Sustainable Development Goal of ending the tuberculosis epidemic by 2030, new treatments are urgently required. We previously reported the discovery of 49, a preclinical candidate that acted through inhibition of the Mycobacterium tuberculosis lysyl tRNA synthetase (LysRS). In this report, the full medicinal chemistry program is reviewed from the original hit through to the optimized lead. The work was guided by the first crystal structures of M. tuberculosis LysRS. The physicochemical and pharmacokinetic properties were optimized to afford compounds suitable for evaluation in mouse efficacy models of tuberculosis and with the potential for clinical development.	Aug 2025
I03-Macromolecular Crystallography	Cryptosporidium lysyl-tRNA synthetase inhibitors define the interplay between solubility and permeability required to achieve efficacy Nicola Caldwell , Caroline Peet , Peter Miller , Beatrice L. Colon , Malcolm G. Taylor , Mattia Cocco , Alice Dawson , Iva Lukac , Jose E. Teixeira , Lee Robinson , Laura Frame , Simona Seizova , Sebastian Damerow , Fabio Tamaki , John Post , Jennifer Riley , Nicole Mutter , Jack C. Hanna , Liam Ferguson , Xiao Hu , Michele Tinti , Barbara Forte , Neil R. Norcross , Peter S. Campbell , Nina Svensen , Flora C. Caldwell , Chimed Jansen , Vincent Postis , Kevin D. Read , Christopher D. Huston , Ian H. Gilbert , Beatriz Baragaña , Mattie C. Pawlowic Science Translational Medicine 16 DOI: 10.1126/scitranslmed.adm8631 Diamond Proposal Number(s): [19844] Show Abstract ▼ Abstract: Cryptosporidiosis is a diarrheal disease caused by infection with Cryptosporidium spp. parasites and is a leading cause of death in malnourished children worldwide. The only approved treatment, nitazoxanide, has limited efficacy in this at-risk patient population. Additional safe therapeutics are urgently required to tackle this unmet medical need. However, the development of anti-cryptosporidial drugs is hindered by a lack of understanding of the optimal compound properties required to treat this gastrointestinal infection. To address this knowledge gap, a diverse set of potent lysyl-tRNA synthetase inhibitors was profiled to identify optimal physicochemical and pharmacokinetic properties required for efficacy in a chronic mouse model of infection. The results from this comprehensive study illustrated the importance of balancing solubility and permeability to achieve efficacy in vivo. Our results establish in vitro criteria for solubility and permeability that are predictive of compound efficacy in vivo to guide the optimization of anti-cryptosporidial drugs. Two compounds from chemically distinct series (DDD489 and DDD508) were identified as demonstrating superior efficacy and prioritized for further evaluation. Both compounds achieved marked parasite reduction in immunocompromised mouse models and a disease-relevant calf model of infection. On the basis of these promising data, these compounds have been selected for progression to preclinical safety studies, expanding the portfolio of potential treatments for this neglected infectious disease.	Oct 2024
I04-1-Macromolecular Crystallography (fixed wavelength) I24-Microfocus Macromolecular Crystallography	Identification and optimization of novel inhibitors of the polyketide synthase 13 thioesterase domain with antitubercular activity Simon R. Green , Caroline Wilson , Thomas C. Eadsforth , Avinash S. Punekar , Fabio K. Tamaki , Gavin Wood , Nicola Caldwell , Barbara Forte , Neil R. Norcross , Michael Kiczun , John M. Post , Eva Maria Lopez-Román , Curtis A. Engelhart , Iva Lukac , Fabio Zuccotto , Ola Epemolu , Helena I. M. Boshoff , Dirk Schnappinger , Chris Walpole , Ian H. Gilbert , Kevin D. Read , Paul G. Wyatt , Beatriz Baragaña Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.3c01514 Open Access Show Abstract ▼ Abstract: There is an urgent need for new tuberculosis (TB) treatments, with novel modes of action, to reduce the incidence/mortality of TB and to combat resistance to current treatments. Through both chemical and genetic methodologies, polyketide synthase 13 (Pks13) has been validated as essential for mycobacterial survival and as an attractive target for Mycobacterium tuberculosis growth inhibitors. A benzofuran series of inhibitors that targeted the Pks13 thioesterase domain, failed to progress to preclinical development due to concerns over cardiotoxicity. Herein, we report the identification of a novel oxadiazole series of Pks13 inhibitors, derived from a high-throughput screening hit and structure-guided optimization. This new series binds in the Pks13 thioesterase domain, with a distinct binding mode compared to the benzofuran series. Through iterative rounds of design, assisted by structural information, lead compounds were identified with improved antitubercular potencies (MIC < 1 μM) and in vitro ADMET profiles.	Nov 2023
I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs Simon R. Green , Susan H. Davis , Sebastian Damerow , Curtis A. Engelhart , Michael Mathieson , Beatriz Baragaña , David A. Robinson , Jevgenia Tamjar , Alice Dawson , Fabio K. Tamaki , Kirsteen I. Buchanan , John Post , Karen Dowers , Sharon M. Shepherd , Chimed Jansen , Fabio Zuccotto , Ian H. Gilbert , Ola Epemolu , Jennifer Riley , Laste Stojanovski , Maria Osuna-Cabello , Esther Pérez-Herrán , María José Rebollo , Laura Guijarro López , Patricia Casado Castro , Isabel Camino , Heather C. Kim , James M. Bean , Navid Nahiyaan , Kyu Y. Rhee , Qinglan Wang , Vee Y. Tan , Helena I. M. Boshoff , Paul J. Converse , Si-Yang Li , Yong S. Chang , Nader Fotouhi , Anna M. Upton , Eric L. Nuermberger , Dirk Schnappinger , Kevin D. Read , Lourdes Encinas , Robert H. Bates , Paul G. Wyatt , Laura A. T. Cleghorn Nature Communications 13 DOI: 10.1038/s41467-022-33736-5 Diamond Proposal Number(s): [14980] Open Access Show Abstract ▼ Abstract: Tuberculosis is a major global cause of both mortality and financial burden mainly in low and middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an urgent need for the development of new, safe and effective treatments. Here the development of a drug-like series based on a fused dihydropyrrolidino-pyrimidine scaffold is described. The series has been developed against M. tuberculosis lysyl-tRNA synthetase (LysRS) and cellular studies support this mechanism of action. DDD02049209, the lead compound, is efficacious in mouse models of acute and chronic tuberculosis and has suitable physicochemical, pharmacokinetic properties and an in vitro safety profile that supports further development. Importantly, preliminary analysis using clinical resistant strains shows no pre-existing clinical resistance towards this scaffold.	Oct 2022
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	A brain-permeable inhibitor of the neurodegenerative disease target kynurenine 3-monooxygenase prevents accumulation of neurotoxic metabolites Shaowei Zhang , Michiyo Sakuma , Girdhar S. Deora , Colin Levy , Alex Klausing , Carlo Breda , Kevin D. Read , Chris D. Edlin , Benjamin P. Ross , Marina Wright Muelas , Philip J. Day , Stephen O’hagan , Douglas B. Kell , Robert Schwarcz , David Leys , Derren J. Heyes , Flaviano Giorgini , Nigel S. Scrutton Communications Biology 2 DOI: 10.1038/s42003-019-0520-5 Diamond Proposal Number(s): [8997, 12788] Open Access Show Abstract ▼ Abstract: Dysregulation of the kynurenine pathway (KP) leads to imbalances in neuroactive metabolites associated with the pathogenesis of several neurodegenerative disorders, including Huntington’s disease (HD). Inhibition of the enzyme kynurenine 3-monooxygenase (KMO) in the KP normalises these metabolic imbalances and ameliorates neurodegeneration and related phenotypes in several neurodegenerative disease models. KMO is thus a promising candidate drug target for these disorders, but known inhibitors are not brain permeable. Here, 19 new KMO inhibitors have been identified. One of these (1) is neuroprotective in a Drosophila HD model but is minimally brain penetrant in mice. The prodrug variant (1b) crosses the blood–brain barrier, releases 1 in the brain, thereby lowering levels of 3-hydroxykynurenine, a toxic KP metabolite linked to neurodegeneration. Prodrug 1b will advance development of targeted therapies against multiple neurodegenerative and neuroinflammatory diseases in which KP likely plays a role, including HD, Alzheimer’s disease, and Parkinson’s disease.	Jul 2019
I24-Microfocus Macromolecular Crystallography	Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis Beatriz Baragaña , Barbara Forte , Ryan Choi , Stephen Nakazawa Hewitt , Juan A. Bueren-Calabuig , Joao Pedro Pisco , Caroline Peet , David M. Dranow , David A. Robinson , Chimed Jansen , Neil R. Norcross , Sumiti Vinayak , Mark Anderson , Carrie F. Brooks , Caitlin A. Cooper , Sebastian Damerow , Michael Delves , Karen Dowers , James Duffy , Thomas E. Edwards , Irene Hallyburton , Benjamin G. Horst , Matthew A. Hulverson , Liam Ferguson , María Belén Jiménez-Díaz , Rajiv S. Jumani , Donald D. Lorimer , Melissa S. Love , Steven Maher , Holly Matthews , Case W. Mcnamara , Peter Miller , Sandra O’neill , Kayode K. Ojo , Maria Osuna-Cabello , Erika Pinto , John Post , Jennifer Riley , Matthias Rottmann , Laura M. Sanz , Paul Scullion , Arvind Sharma , Sharon M. Shepherd , Yoko Shishikura , Frederick R. C. Simeons , Erin E. Stebbins , Laste Stojanovski , Ursula Straschil , Fabio K. Tamaki , Jevgenia Tamjar , Leah S. Torrie , Amélie Vantaux , Benoît Witkowski , Sergio Wittlin , Manickam Yogavel , Fabio Zuccotto , Iñigo Angulo-Barturen , Robert Sinden , Jake Baum , Francisco-Javier Gamo , Pascal Mäser , Dennis E. Kyle , Elizabeth A. Winzeler , Peter J. Myler , Paul G. Wyatt , David Floyd , David Matthews , Amit Sharma , Boris Striepen , Christopher D. Huston , David W. Gray , Alan H. Fairlamb , Andrei V. Pisliakov , Chris Walpole , Kevin D. Read , Wesley C. Van Voorhis , Ian H. Gilbert Proceedings Of The National Academy Of Sciences 116, 7015 - 7020 DOI: 10.1073/pnas.1814685116 Diamond Proposal Number(s): [10071] Open Access Show Abstract ▼ Abstract: Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage Plasmodium falciparum and Cryptosporidium parvum in cell-culture studies. Target deconvolution in P. falciparum has shown that cladosporin inhibits lysyl-tRNA synthetase (PfKRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both PfKRS1 and C. parvum KRS (CpKRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED90 = 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between PfKRS1 and CpKRS. This series of compounds inhibit CpKRS and C. parvum and Cryptosporidium hominis in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for PfKRS1 and CpKRS vs. (human) HsKRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis.	Apr 2019
I03-Macromolecular Crystallography	A molecular hybridization approach for the design of potent, highly selective, and brain-penetrant n-myristoyltransferase inhibitors Justin R. Harrison , Stephen Brand , Victoria Smith , David A. Robinson , Stephen Thompson , Alasdair Smith , Kenneth Davies , Ngai Mok , Leah S. Torrie , Iain Collie , Irene Hallyburton , Suzanne Norval , Frederick R. C. Simeons , Laste Stojanovski , Julie A. Frearson , Ruth Brenk , Paul G. Wyatt , Ian H. Gilbert , Kevin D. Read Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.8b00884 Diamond Proposal Number(s): [7705] Open Access Show Abstract ▼ Abstract: Crystallography has guided the hybridization of two series of Trypanosoma brucei N-myristoyltransferase (NMT) inhibitors, leading to a novel highly selective series. The effect of combining the selectivity enhancing elements from two pharmacophores is shown to be additive and has led to compounds that have greater than 1000-fold selectivity for TbNMT vs HsNMT. Further optimization of the hybrid series has identified compounds with significant trypanocidal activity capable of crossing the blood–brain barrier. By using CF-1 mdr1a deficient mice, we were able to demonstrate full cures in vivo in a mouse model of stage 2 African sleeping sickness. This and previous work provides very strong validation for NMT as a drug target for human African trypanosomiasis in both the peripheral and central nervous system stages of disease.	Sep 2018
I04-1-Macromolecular Crystallography (fixed wavelength)	Optimization of a “bump-and-hole” approach to allele-selective BET bromodomain inhibition Andrew Runcie , Michael Zengerle , Kwok-Ho Chan , Andrea Testa , Lars Van Beurden , Matthias Baud , Ola Epemolu , Lucy Ellis , Kevin Read , Victoria Coulthard , Alex Brien , Alessio Ciulli Chemical Science DOI: 10.1039/C7SC02536J Diamond Proposal Number(s): [10071] Open Access Show Abstract ▼ Abstract: Allele-specific chemical genetics enables selective inhibition within families of highly-conserved proteins. The four BET (bromodomain & extra-terminal domain) proteins – BRD2, BRD3, BRD4 and BRDT bind acetylated chromatin via their bromodomains and regulate processes such as cell proliferation and inflammation. BET bromodomains are of particular interest, as they are attractive therapeutic targets but existing inhibitors are pan-selective. We previously established a bump-&-hole system for the BET bromodomains, pairing a leucine/alanine mutation with an ethyl-derived analogue of an established benzodiazepine scaffold. Here we optimize upon this system with the introduction of a more conservative and less disruptive leucine/valine mutation. Extensive structure-activity-relationships of diverse benzodiazepine analogues guided the development of potent, mutant-selective inhibitors with desirable physiochemical properties. The active enantiomer of our best compound – 9-ME-1 – shows ~200 nM potency, >100-fold selectivity for the L/V mutant over wild-type and excellent DMPK properties. Through a variety of in vitro and cellular assays we validate the capabilities of our optimized system, and then utilize it to compare the relative importance of the first and second bromodomains to chromatin binding. These experiments confirm the primacy of the first bromodomain in all BET proteins, but also significant variation in the importance of the second bromodomain. We also show that, despite having a minor role in chromatin recognition, BRD4 BD2 is still essential for gene expression , likely through the recruitment of non-histone proteins. The disclosed inhibitor:mutant pair provides a powerful tool for future cellular and in vivo target validation studies.	Jan 2018
I02-Macromolecular Crystallography I04-Macromolecular Crystallography	Chemical validation of methionyl-trna synthetase as a druggable target in Leishmania donovani Leah S. Torrie , Stephen Brand , David A. Robinson , Eun Jung Ko , Laste Stojanovski , Frederick R. C. Simeons , Susan Wyllie , John Thomas , Lucy Ellis , Maria Osuna-Cabello , Ola Epemolu , Andrea Nühs , Jennifer Riley , Lorna Maclean , Sujatha Manthri , Kevin D. Read , Ian H. Gilbert , Alan H. Fairlamb , Manu De Rycker Acs Infectious Diseases DOI: 10.1021/acsinfecdis.7b00047 Diamond Proposal Number(s): [8268] Open Access Show Abstract ▼ Abstract: Methionyl-tRNA synthetase (MetRS) has been chemically validated as a drug target in the kinetoplastid parasite Trypanosoma brucei. In the present study, we investigate the validity of this target in the related trypanosomatid Leishmania donovani. Following development of a robust high-throughput compatible biochemical assay, a compound screen identified DDD806905 as a highly potent inhibitor of LdMetRS (Ki of 18 nM). Crystallography revealed this compound binds to the methionine pocket of MetRS with enzymatic studies confirming DDD806905 displays competitive inhibition with respect to methionine and mixed inhibition with respect to ATP binding. DDD806905 showed activity, albeit with different levels of potency, in various Leishmania cell-based viability assays, with on-target activity observed in both Leishmania promastigote cell assays and a Leishmania tarentolae in vitro translation assay. Unfortunately, this compound failed to show efficacy in an animal model of leishmaniasis. We investigated the potential causes for the discrepancies in activity observed in different Leishmania cell assays and the lack of efficacy in the animal model and found that high protein binding as well as sequestration of this dibasic compound into acidic compartments may play a role. Despite medicinal chemistry efforts to address the dibasic nature of DDD806905 and analogues, no progress could be achieved with the current chemical series. Although DDD806905 is not a developable antileishmanial compound, MetRS remains an attractive antileishmanial drug target.	Oct 2017
I04-1-Macromolecular Crystallography (fixed wavelength)	Group-based optimization of potent and cell-active inhibitors of the von Hippel–Lindau (VHL) e3 ubiquitin ligase Pedro Soares , Morgan S. Gadd , Julianty Frost , Carles Galdeano , Lucy C. J. Ellis , Ola Epemolu , Sonia Rocha , Kevin D. Read , Alessio Ciulli Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.7b00675 Diamond Proposal Number(s): [10071] Open Access Show Abstract ▼ Abstract: The von Hippel–Lindau tumor suppressor protein is the substrate binding subunit of the VHL E3 ubiquitin ligase, which targets hydroxylated α subunit of hypoxia inducible factors (HIFs) for ubiquitination and subsequent proteasomal degradation. VHL is a potential target for treating anemia and ischemic diseases, motivating the development of inhibitors of the VHL:HIF-α protein-protein interaction. Additionally, bifunctional proteolysis targeting chimeras (PROTACs) containing a VHL ligand can hijack the E3 ligase activity to induce degradation of target proteins. We report the structure-guided design and group-based optimization of a series of VHL inhibitors with low nanomolar potencies and improved cellular permeability. Structure-activity relationships led to the discovery of potent inhibitors 10 and chemical probe VH298, with dissociation constants <100 nM, which induced marked HIF-1α intracellular stabilization. Our study provides new chemical tools to probe the VHL-HIF pathways, and new VHL ligands for next-generation PROTACs.	Aug 2017

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