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Dive into the research topics where Jonathan M. Large is active.

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Featured researches published by Jonathan M. Large.


Journal of Medicinal Chemistry | 2010

Imidazo[4,5-b]pyridine Derivatives As Inhibitors of Aurora Kinases: Lead Optimization Studies toward the Identification of an Orally Bioavailable Preclinical Development Candidate

Vassilios Bavetsias; Jonathan M. Large; Chongbo Sun; Nathalie Bouloc; Magda N. Kosmopoulou; Mizio Matteucci; Nicola E. Wilsher; Vanessa Martins; Jóhannes Reynisson; Butrus Atrash; Amir Faisal; Frederique Urban; Melanie Valenti; Alexis de Haven Brandon; Gary Box; Florence I. Raynaud; Paul Workman; Suzanne A. Eccles; Richard Bayliss; Julian Blagg; Spiros Linardopoulos; Edward McDonald

Lead optimization studies using 7 as the starting point led to a new class of imidazo[4,5-b]pyridine-based inhibitors of Aurora kinases that possessed the 1-benzylpiperazinyl motif at the 7-position, and displayed favorable in vitro properties. Cocrystallization of Aurora-A with 40c (CCT137444) provided a clear understanding into the interactions of this novel class of inhibitors with the Aurora kinases. Subsequent physicochemical property refinement by the incorporation of solubilizing groups led to the identification of 3-((4-(6-bromo-2-(4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)piperazin-1-yl)methyl)-5-methylisoxazole (51, CCT137690) which is a potent inhibitor of Aurora kinases (Aurora-A IC(50) = 0.015 +/- 0.003 muM, Aurora-B IC(50) = 0.025 muM, Aurora-C IC(50) = 0.019 muM). Compound 51 is highly orally bioavailable, and in in vivo efficacy studies it inhibited the growth of SW620 colon carcinoma xenografts following oral administration with no observed toxicities as defined by body weight loss.


ACS Chemical Biology | 2011

Monocyclic β-lactams are selective, mechanism-based inhibitors of rhomboid intramembrane proteases.

Olivier A. Pierrat; Kvido Strisovsky; Yonka Christova; Jonathan M. Large; Keith H. Ansell; Nathalie Bouloc; Ela Smiljanic; Matthew Freeman

Rhomboids are relatively recently discovered intramembrane serine proteases that are conserved throughout evolution. They have a wide range of biological functions, and there is also much speculation about their potential medical relevance. Although rhomboids are weakly inhibited by some broad-spectrum serine protease inhibitors, no potent and specific inhibitors have been identified for these enzymes, which are mechanistically distinct from and evolutionarily unrelated to the classical soluble serine proteases. Here we report a new biochemical assay for rhomboid function based on the use of quenched fluorescent substrate peptides. We have developed this assay into a high-throughput format and have undertaken an inhibitor and activator screen of approximately 58,000 small molecules. This has led to the identification of a new class of rhomboid inhibitors, a series of monocyclic β-lactams, which are more potent than any previous inhibitor. They show selectivity, both for rhomboids over the soluble serine protease chymotrypsin and also, importantly, between different rhomboids; they can inhibit mammalian as well as bacterial rhomboids; and they are effective both in vitro and in vivo. These compounds represent important templates for further inhibitor development, which could have an impact both on biological understanding of rhomboid function and potential future drug development.


Bioorganic & Medicinal Chemistry Letters | 2010

Structure-Based Design of Imidazo[1,2-A]Pyrazine Derivatives as Selective Inhibitors of Aurora-A Kinase in Cells.

Nathalie Bouloc; Jonathan M. Large; Magda N. Kosmopoulou; Chongbo Sun; Amir Faisal; Mizio Matteucci; Jóhannes Reynisson; Nathan Brown; Butrus Atrash; Julian Blagg; Edward McDonald; Spiros Linardopoulos; Richard Bayliss; Vassilios Bavetsias

Co-crystallisation of the imidazo[1,2-a]pyrazine derivative 15 (3-chloro-N-(4-morpholinophenyl)-6-(pyridin-3-yl)imidazo[1,2-a]pyrazin-8-amine) with Aurora-A provided an insight into the interactions of this class of compound with Aurora kinases. This led to the design and synthesis of potent Aurora-A inhibitors demonstrating up to 70-fold selectivity in cell-based Aurora kinase pharmacodynamic biomarker assays.


Bioorganic & Medicinal Chemistry | 2011

Preparation and evaluation of trisubstituted pyrimidines as phosphatidylinositol 3-kinase inhibitors. 3-Hydroxyphenol analogues and bioisosteric replacements

Jonathan M. Large; Jane E. Torr; Florence I. Raynaud; Paul A. Clarke; Angela Hayes; Francesca Di Stefano; Frederique Urban; Stephen J. Shuttleworth; Nahid Saghir; Peter Sheldrake; Paul Workman; Edward McDonald

Two classes of trisubstituted pyrimidines related to PI-103 1 have been prepared and their inhibitory activities against phosphatidylinositol 3-kinase (PI3K) p110α were determined. From those with direct 6-aryl substitution compound 11a was the most potent inhibitor with an IC₅₀ value of 62 nM, and showed similar activity against other class 1a PI3K isoforms tested, p110β and p110γ. When a linking chain was introduced, as in the second exemplified class, compound 15f inhibited p110α with IC₅₀ 142 nM, and showed greater selectivity towards p110α. Compounds of both classes showed promising inhibition of cellular proliferation in IGROV-1 ovarian cancer cells. Among compounds designed to replace the 3-phenolic motif with structural isosteres, analogues incorporating a 4-indazolyl group possessed enzyme and cellular activities comparable to the parent phenols.


Nature Communications | 2017

A potent series targeting the malarial cGMP-dependent protein kinase clears infection and blocks transmission

David A. Baker; Lindsay B. Stewart; Jonathan M. Large; Paul W. Bowyer; Keith H. Ansell; María Belén Jiménez-Díaz; Majida El Bakkouri; Kristian Birchall; Koen J. Dechering; Nathalie Bouloc; Peter J. Coombs; David Whalley; Denise J. Harding; Ela Smiljanic-Hurley; Mary Wheldon; Eloise M. Walker; Johannes T. Dessens; María J. Lafuente; Laura Sanz; Francisco-Javier Gamo; Santiago Ferrer; Raymond Hui; Teun Bousema; Iñigo Angulo-Barturen; Andy Merritt; Simon L. Croft; Winston Gutteridge; Catherine A. Kettleborough; Simon A. Osborne

To combat drug resistance, new chemical entities are urgently required for use in next generation anti-malarial combinations. We report here the results of a medicinal chemistry programme focused on an imidazopyridine series targeting the Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG). The most potent compound (ML10) has an IC50 of 160 pM in a PfPKG kinase assay and inhibits P. falciparum blood stage proliferation in vitro with an EC50 of 2.1 nM. Oral dosing renders blood stage parasitaemia undetectable in vivo using a P. falciparum SCID mouse model. The series targets both merozoite egress and erythrocyte invasion, but crucially, also blocks transmission of mature P. falciparum gametocytes to Anopheles stephensi mosquitoes. A co-crystal structure of PvPKG bound to ML10, reveals intimate molecular contacts that explain the high levels of potency and selectivity we have measured. The properties of this series warrant consideration for further development to produce an antimalarial drug.Protein kinases are promising drug targets for treatment of malaria. Here, starting with a medicinal chemistry approach, Baker et al. generate an imidazopyridine that selectively targets Plasmodium falciparum PKG, inhibits blood stage parasite growth in vitro and in mice and blocks transmission to mosquitoes.


Biochemical and Biophysical Research Communications | 2017

Terbinafine is a novel and selective activator of the two-pore domain potassium channel TASK3

Paul D. Wright; Emma L. Veale; David McCoull; David Tickle; Jonathan M. Large; Emma Ococks; Gemma Gothard; Catherine A. Kettleborough; Alistair Mathie; Jeffrey Jerman

Two-pore domain potassium channels (K2Ps) are characterized by their four transmembrane domain and two-pore topology. They carry background (or leak) potassium current in a variety of cell types. Despite a number of important roles there is currently a lack of pharmacological tools with which to further probe K2P function. We have developed a cell-based thallium flux assay, using baculovirus delivered TASK3 (TWIK-related acid-sensitive K+ channel 3, KCNK9, K2P9.1) with the aim of identifying novel, selective TASK3 activators. After screening a library of 1000 compounds, including drug-like and FDA approved molecules, we identified Terbinafine as an activator of TASK3. In a thallium flux assay a pEC50 of 6.2 ( ±0.12) was observed. When Terbinafine was screened against TASK2, TREK2, THIK1, TWIK1 and TRESK no activation was observed in thallium flux assays. Several analogues of Terbinafine were also purchased and structure activity relationships examined. To confirm Terbinafines activation of TASK3 whole cell patch clamp electrophysiology was carried out and clear potentiation observed in both the wild type channel and the pathophysiological, Birk-Barel syndrome associated, G236R TASK3 mutant. No activity at TASK1 was observed in electrophysiology studies. In conclusion, we have identified the first selective activator of the two-pore domain potassium channel TASK3.


Combinatorial Chemistry & High Throughput Screening | 2009

Design and Combinatorial Synthesis of a Library of Methylenesulfonamides and Related Compounds as Potential Kinase Inhibitors

Jane E. Torr; Jonathan M. Large; Edward McDonald

An effective parallel solid phase route to methylenesulfonamides and amides bearing a wide variety of substituents is described. The three key reaction steps were reductive amination of a haloheteroaromatic aldehyde onto a benzhydrylamine type polystyrene resin, sulfonamide or amide formation and palladium catalysed transformation of the remaining heteroaromatic halogen. A process of virtual library design and filtering, together with solution and solid phase optimizations, aided the preparation of several novel drug-like product classes in high purities and should allow access to a variety of further useful analogues.


Bioorganic & Medicinal Chemistry Letters | 2018

Trisubstituted thiazoles as potent and selective inhibitors of Plasmodium falciparum protein kinase G (PfPKG)

Denise J. Tsagris; Kristian Birchall; Nathalie Bouloc; Jonathan M. Large; Andy Merritt; Ela Smiljanic-Hurley; Mary Wheldon; Keith H. Ansell; Catherine A. Kettleborough; David Paul Whalley; Lindsay B. Stewart; Paul W. Bowyer; David A. Baker; Simon A. Osborne

A series of trisubstituted thiazoles have been identified as potent inhibitors of Plasmodium falciparum (Pf) cGMP-dependent protein kinase (PfPKG) through template hopping from known Eimeria PKG (EtPKG) inhibitors. The thiazole series has yielded compounds with improved potency, kinase selectivity and good in vitro ADME properties. These compounds could be useful tools in the development of new anti-malarial drugs in the fight against drug resistant malaria.


Archive | 2008

Pyrimidine derivatives as inhibitors of phosphatidylinositol-3-kinase

Paul John Goldsmith; Timothy Colin Hancox; Neil Anthony Pegg; Stephen Joseph Shuttleworth; Elsa Amandine Dechaux; Stephen Price; Jonathan M. Large; Edward McDonald


Archive | 2008

2-MORPHOLIN-4-YL-PYRIMIDINES AS PI3K INHIBITORS

Paul John Goldsmith; Timothy Colin Hancox; Neil Anthony Pegg; Stephen Joseph Shuttleworth; Jonathan M. Large; Edward McDonald

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Edward McDonald

Institute of Cancer Research

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Jane E. Torr

Institute of Cancer Research

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Amir Faisal

Institute of Cancer Research

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Andy Merritt

Medical Research Council

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Butrus Atrash

Institute of Cancer Research

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Chongbo Sun

Institute of Cancer Research

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Florence I. Raynaud

Institute of Cancer Research

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Frederique Urban

Institute of Cancer Research

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