Stuart Thomas Onions
University of Nottingham
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Featured researches published by Stuart Thomas Onions.
Journal of Medicinal Chemistry | 2016
Stuart Thomas Onions; Kazuhiro Ito; Catherine Elisabeth Charron; Richard J. Brown; Marie A. Colucci; Fritz Frickel; George William Hardy; Kevin Joly; John King-Underwood; Yasuo Kizawa; Ian Knowles; P. John Murray; Andrew Richard Novak; Anjna Rani; Garth Rapeport; Alun John Smith; Peter N. Strong; David Michel Adrien Taddei
The discovery of a novel series of therapeutic agents that has been designed and optimized for treating chronic obstructive pulmonary disease is reported. The pharmacological strategy was based on the identification of compounds that inhibit a defined subset of kinase enzymes modulating inflammatory processes that would be effective against steroid refractory disease and exhibit a sustained duration of action after inhaled delivery.
Antimicrobial Agents and Chemotherapy | 2017
Matthew Coates; Daniel Brookes; Young In Kim; Heather Allen; Euan Alexander Fraser Fordyce; Elizabeth A. Meals; Thomas Colley; Claire Lise Ciana; Guillaume F. Parra; Vladimir Sherbukhin; Jennifer A. Stockwell; Jennifer C. Thomas; S. Fraser Hunt; Lauren Anderson-Dring; Stuart Thomas Onions; Lindsey Cass; Peter J. Murray; Kazuhiro Ito; Pete Strong; John P. DeVincenzo; Garth Rapeport
ABSTRACT Although respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants and young children, attempts to develop an effective therapy have so far proved unsuccessful. Here we report the preclinical profiles of PC786, a potent nonnucleoside RSV L protein polymerase inhibitor, designed for inhalation treatment of RSV infection. PC786 demonstrated a potent and selective antiviral activity against laboratory-adapted or clinical isolates of RSV-A (50% inhibitory concentration [IC50], <0.09 to 0.71 nM) and RSV-B (IC50, 1.3 to 50.6 nM), which were determined by inhibition of cytopathic effects in HEp-2 cells without causing detectable cytotoxicity. The underlying inhibition of virus replication was confirmed by PCR analysis. The effects of PC786 were largely unaffected by the multiplicity of infection (MOI) and were retained in the face of established RSV replication in a time-of-addition study. Persistent anti-RSV effects of PC786 were also demonstrated in human bronchial epithelial cells. In vivo intranasal once daily dosing with PC786 was able to reduce the virus load to undetectable levels in lung homogenates from RSV-infected mice and cotton rats. Treatment with escalating concentrations identified a dominant mutation in the L protein (Y1631H) in vitro. In addition, PC786 potently inhibited RSV RNA-dependent RNA polymerase (RdRp) activity in a cell-free enzyme assay and minigenome assay in HEp-2 cells (IC50, 2.1 and 0.5 nM, respectively). Thus, PC786 was shown to be a potent anti-RSV agent via inhibition of RdRp activity, making topical treatment with this compound a novel potential therapy for the treatment of human RSV infections.
Antimicrobial Agents and Chemotherapy | 2017
Thomas Colley; Alexandre Alanio; Steven L. Kelly; Gurpreet Sehra; Yasuo Kizawa; Andrew G. S. Warrilow; Josie E. Parker; Diane E. Kelly; Genki Kimura; Lauren Anderson-Dring; Takahiro Nakaoki; Mihiro Sunose; Stuart Thomas Onions; Damien Crepin; Franz Lagasse; Matthew Crittall; Jonathan Shannon; Michael Cooke; Stéphane Bretagne; John King-Underwood; John Murray; Kazuhiro Ito; Pete Strong; Garth Rapeport
ABSTRACT The profile of PC945, a novel triazole antifungal designed for administration via inhalation, was assessed in a range of in vitro and in vivo studies. PC945 was characterized as a potent, tightly binding inhibitor of Aspergillus fumigatus sterol 14α-demethylase (CYP51A and CYP51B) activity (50% inhibitory concentrations [IC50s], 0.23 μM and 0.22 μM, respectively) with characteristic type II azole binding spectra. Against 96 clinically isolated A. fumigatus strains, the MIC values of PC945 ranged from 0.032 to >8 μg/ml, while those of voriconazole ranged from 0.064 to 4 μg/ml. Spectrophotometric analysis of the effects of PC945 against itraconazole-susceptible and -resistant A. fumigatus growth yielded IC50 (determined based on optical density [OD]) values of 0.0012 to 0.034 μg/ml, whereas voriconazole (0.019 to >1 μg/ml) was less effective than PC945. PC945 was effective against a broad spectrum of pathogenic fungi (with MICs ranging from 0.0078 to 2 μg/ml), including Aspergillus terreus, Trichophyton rubrum, Candida albicans, Candida glabrata, Candida krusei, Cryptococcus gattii, Cryptococcus neoformans, and Rhizopus oryzae (1 or 2 isolates each). In addition, when A. fumigatus hyphae or human bronchial cells were treated with PC945 and then washed, PC945 was found to be absorbed quickly into both target and nontarget cells and to produce persistent antifungal effects. Among temporarily neutropenic immunocompromised mice infected with A. fumigatus intranasally, 50% of the animals survived until day 7 when treated intranasally with PC945 at 0.56 μg/mouse, while posaconazole showed similar effects (44%) at 14 μg/mouse. This profile affirms that topical treatment with PC945 should provide potent antifungal activity in the lung.
Journal of Medicinal Chemistry | 2018
Tom D. Heightman; Valerio Berdini; Hannah Braithwaite; Ildiko Maria Buck; Megan Cassidy; Juan Castro; Aurélie Courtin; James E. H. Day; Charlotte East; Lynsey Fazal; Brent Graham; Charlotte Mary Griffiths-Jones; John Lyons; Vanessa Martins; Sandra Muench; Joanne M. Munck; David Norton; Marc O’Reilly; Nick Palmer; Puja Pathuri; Michael Reader; David C. Rees; Sharna J. Rich; Caroline Richardson; Harpreet K. Saini; Neil Thompson; Nicola G. Wallis; Hugh Walton; Nicola E. Wilsher; Alison Jo-Anne Woolford
Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signaling through ERK1/2. Here, we describe the fragment-based generation of ERK1/2 inhibitors that block catalytic phosphorylation of downstream substrates such as RSK but also modulate phosphorylation of ERK1/2 by MEK without directly inhibiting MEK. X-ray crystallographic and biophysical fragment screening followed by structure-guided optimization and growth from the hinge into a pocket proximal to the C-α helix afforded highly potent ERK1/2 inhibitors with excellent kinome selectivity. In BRAF mutant cells, the lead compound suppresses pRSK and pERK levels and inhibits proliferation at low nanomolar concentrations. The lead exhibits tumor regression upon oral dosing in BRAF mutant xenograft models, providing a promising basis for further optimization toward clinical pERK1/2 modulating ERK1/2 inhibitors.
Archive | 2009
Kazuhiro Ito; Peter Strong; William Garth Rapeport; Peter John Murray; John King-Underwood; Stuart Thomas Onions; Simon Christopher Hirst; David Michel Adrien Taddei; Catherine Elisabeth Charron
Archive | 2007
Alan Hastings Drummond; John King-Underwood; Stuart Thomas Onions; Johathan Gareth Williams; Simon Christopher Hirst
Archive | 2010
Kazuhiro Ito; Peter N. Strong; William Garth Rapeport; Peter J. Murray; John King-Underwood; Stuart Thomas Onions; Catherine Elisabeth Charron
Archive | 2009
Kazuhiro Ito; Peter Strong; William Garth Rapeport; John King-Underwood; Stuart Thomas Onions; Peter John Murray; Catherine Elisabeth Charron
Archive | 2011
John King-Underwood; Kazuhiro Ito; Peter Strong; William Garth Rapeport; Catherine Elisabeth Charron; Peter John Murray; Stuart Thomas Onions
Archive | 2007
David Festus Charles Moffat; Simon Christopher Hirst; Stuart Thomas Onions