Cyclofluidic Ltd

Welwyn Garden City, United Kingdom

Cyclofluidic Ltd

Welwyn Garden City, United Kingdom
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Lambert G.K.,University of York | Lambert G.K.,Cyclofluidic Ltd | Duhme-Klair A.-K.,University of York | Morgan T.,Cyclofluidic Ltd | Ramjee M.K.,Cyclofluidic Ltd
Drug Discovery Today | Year: 2013

The story of the inhibition of BCR-ABL as a treatment for chronic myelogenous leukaemia serves to illustrate key aspects of the kinase drug discovery and development process. Firstly, elucidation of the disease mechanism enabled identification of the molecular target(s) which catalysed pharmaceutical research and resulted in Gleevec® (Novartis) as the first FDA approved BCR-ABL inhibitor. However, clinical success was soon tempered by the emergence of drug resistance through various mechanisms. Using rational drug design, several hypotheses were devised to overcome resistance issues leading to the development of second generation inhibitors, providing clinicians and patients with greater therapeutic choice. © 2013 Elsevier Ltd. All rights reserved.


Ramjee M.K.,Cyclofluidic Ltd | Patel S.,Cyclofluidic Ltd
Analytical Biochemistry | Year: 2017

A microfluidic assay for monitoring the inhibition of thrombin peptidase activity was developed. The system, which utilised soluble reagents in continuous-flow injection mode, was configured so as to allow inhibitor titrations via gradient formation. This microfluidic continuous-flow injection titration assay (CFITA) enabled the potency of a set of small-molecule serine peptidase inhibitors (SPIs) to be evaluated. The results, compared to standard microtiter plate (MTP) data, indicated that a microfluidic CFITA provided an efficient and effective method for evaluating compound potency. Crucially, whereas for fast-acting compounds the rank order of potency between the CFITA and MTP methods was preserved, for slow-acting compounds the observed CFITA potencies were significantly lower. These results, in conjunction with data from computer simulations, clearly demonstrated that continuous-flow assays, and perhaps microfluidic assays in general, must take into account binding kinetics when used to assess reaction criteria. © 2017 Elsevier Inc.


Wright P.,Keele University | Wright A.,Cyclofluidic Ltd
Bioanalysis | Year: 2016

There are three main reasons for transferring from an existing bioanalytical assay to an alternative chromatographic method: speed, cost and sensitivity. These represent a challenge to the analyst in that there is an interplay between these three considerations and one factor is often improved at the expense of another. These three factors act as drivers to encourage technology development and support its uptake. The more recently introduced chromatographic technologies may show significant improvements against one of more of these factors relative to conventional 4.6-mm id reversed-phase HPLC. In this article, some of these new chromatographic approaches will be considered in terms of what they can offer the bioanalysts. © 2016 Future Science Ltd.


PubMed | Keele University and Cyclofluidic Ltd
Type: Journal Article | Journal: Bioanalysis | Year: 2016

There are three main reasons for transferring from an existing bioanalytical assay to an alternative chromatographic method: speed, cost and sensitivity. These represent a challenge to the analyst in that there is an interplay between these three considerations and one factor is often improved at the expense of another. These three factors act as drivers to encourage technology development and support its uptake. The more recently introduced chromatographic technologies may show significant improvements against one of more of these factors relative to conventional 4.6-mm id reversed-phase HPLC. In this article, some of these new chromatographic approaches will be considered in terms of what they can offer the bioanalysts.


Desai B.,Cyclofluidic Ltd | Dixon K.,Cyclofluidic Ltd | Farrant E.,Cyclofluidic Ltd | Feng Q.,Cyclofluidic Ltd | And 10 more authors.
Journal of Medicinal Chemistry | Year: 2013

Drug discovery faces economic and scientific imperatives to deliver lead molecules rapidly and efficiently. Using traditional paradigms the molecular design, synthesis, and screening loops enforce a significant time delay leading to inefficient use of data in the iterative molecular design process. Here, we report the application of a flow technology platform integrating the key elements of structure-activity relationship (SAR) generation to the discovery of novel Abl kinase inhibitors. The platform utilizes flow chemistry for rapid in-line synthesis, automated purification, and analysis coupled with bioassay. The combination of activity prediction using Random-Forest regression with chemical space sampling algorithms allows the construction of an activity model that refines itself after every iteration of synthesis and biological result. Within just 21 compounds, the automated process identified a novel template and hinge binding motif with pIC50 > 8 against Abl kinase - both wild type and clinically relevant mutants. Integrated microfluidic synthesis and screening coupled with machine learning design have the potential to greatly reduce the time and cost of drug discovery within the hit-to-lead and lead optimization phases. © 2013 American Chemical Society.


Czechtizky W.,Sanofi S.A. | Dedio J.,Sanofi S.A. | Desai B.,Cyclofluidic Ltd. | Dixon K.,Cyclofluidic Ltd. | And 9 more authors.
ACS Medicinal Chemistry Letters | Year: 2013

A novel integrated discovery platform has been used to synthesize and biologically assay a series of xanthine-derived dipeptidyl peptidase 4 (DPP4) antagonists. Design, synthesis, purification, quantitation, dilution, and bioassay have all been fully integrated to allow continuous automated operation. The system has been validated against a set of known DPP4 inhibitors and shown to give excellent correlation between traditional medicinal chemistry generated biological data and platform data. Each iterative loop of synthesis through biological assay took two hours in total, demonstrating rapid iterative structure-activity relationship generation. © 2013 American Chemical Society.


PubMed | Cyclofluidic Ltd
Type: Journal Article | Journal: Journal of medicinal chemistry | Year: 2013

Drug discovery faces economic and scientific imperatives to deliver lead molecules rapidly and efficiently. Using traditional paradigms the molecular design, synthesis, and screening loops enforce a significant time delay leading to inefficient use of data in the iterative molecular design process. Here, we report the application of a flow technology platform integrating the key elements of structure-activity relationship (SAR) generation to the discovery of novel Abl kinase inhibitors. The platform utilizes flow chemistry for rapid in-line synthesis, automated purification, and analysis coupled with bioassay. The combination of activity prediction using Random-Forest regression with chemical space sampling algorithms allows the construction of an activity model that refines itself after every iteration of synthesis and biological result. Within just 21 compounds, the automated process identified a novel template and hinge binding motif with pIC50 > 8 against Abl kinase--both wild type and clinically relevant mutants. Integrated microfluidic synthesis and screening coupled with machine learning design have the potential to greatly reduce the time and cost of drug discovery within the hit-to-lead and lead optimization phases.

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