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Manchester, United Kingdom

Winter J.J.G.,Astrazeneca | Anderson M.,Astrazeneca | Anderson M.,Waters Corporation | Blades K.,Astrazeneca | And 20 more authors.
Journal of Medicinal Chemistry | Year: 2015

Constitutively active mutant KRas displays a reduced rate of GTP hydrolysis via both intrinsic and GTPase-activating protein-catalyzed mechanisms, resulting in the perpetual activation of Ras pathways. We describe a fragment screening campaign using X-ray crystallography that led to the discovery of three fragment binding sites on the Ras:SOS complex. The identification of tool compounds binding at each of these sites allowed exploration of two new approaches to Ras pathway inhibition by stabilizing or covalently modifying the Ras:SOS complex to prevent the reloading of Ras with GTP. Initially, we identified ligands that bound reversibly to the Ras:SOS complex in two distinct sites, but these compounds were not sufficiently potent inhibitors to validate our stabilization hypothesis. We conclude by demonstrating that covalent modification of Cys118 on Ras leads to a novel mechanism of inhibition of the SOS-mediated interaction between Ras and Raf and is effective at inhibiting the exchange of labeled GDP in both mutant (G12C and G12V) and wild type Ras. © 2015 American Chemical Society.

C4X Discovery | Entity website

Oral Orexin-1 Antagonist The Orexin-1 receptor is considered to be central to the brains craving and reward pathways with pre-clinical efficacy observed in multiple addiction models. However, to date no drug candidate that targets Orexin-1 has progressed into clinical development, in large part due to the difficulty in identifying candidates that are specific only to Orexin-1 ...

C4X Discovery | Entity website

17 March, 2016 - C4X Discovery Holdings plc (AIM: C4XD), an innovative drug discovery and development company, today announces its interim unaudited results for the six months ended 31 January 2016. Corporate highlights Dr Clive Dix appointed as Executive Chairman to implement strategy of building the worlds most productive drug discovery and development company ...

Dotmatics' platform to support internal and external collaborative research at C4X Discovery Dotmatics, the leading provider of scientific informatics solutions and services, announced today that after an exhaustive evaluation process, C4X Discovery has selected the Dotmatics Platform for its scientific data management and collaboration hub. C4X Discovery is focused on improving the efficiency and productivity of drug discovery and design through the use of NMR-based technology. The implementation of the Dotmatics Platform will facilitate their assay and 'meta' data management and analysis. C4X Discovery uses NMR to determine the dynamic 3D-conformations of biologically relevant molecules in solution. This simplifies rational drug discovery by complementing protein structure elucidation and/or computational chemistry workflows. C4X Discovery will use the Dotmatics Platform to store, analyse and manage its chemical and biology data. Register will be used to record samples and associated information while Studies will be the main hub for assay design, capture, validation and analysis. The powerful combination of web-based tools Browser and Vortex will be used to rapidly access information in real time, find trends and thus make real time decisions. The easy accessibility and high security of Dotmatics' cloud-based solutions provides C4X Discovery with a collaborative environment in which to share information internally, as well as with external partners from Academia and other Pharmaceutical and Biotech organisations. "We look forward to working with Dotmatics. Their informatics solutions significantly enhance our ability to maximise the value of our technology platform and our portfolio," said Piers Morgan, CEO of C4X Discovery. "C4X Discovery has a very interesting and novel approach to rational drug discovery and we are delighted to provide the informatics infrastructure to support their research," said Dr Stephen Gallagher, CEO of Dotmatics. "This deployment is testimony to the ability of our Platform to adapt to different workflows and deliver immediate value to our customers." Dotmatics is a leading global scientific informatics software and services provider, delivering solutions tailored to the modern, highly collaborative and mobile scientific environments. The company provides solutions to several vertical markets, including the pharmaceutical, biotechnology, academia, food and beverage, oil and gas and agrochemical industries. Dotmatics' enterprise solutions are flexible, scalable and configurable, providing effective scientific information management across entire organisations, from discovery research to development and early manufacturing. Dotmatics has significant expertise in scientific informatics, including database management for chemistry and biologics, electronic laboratory notebooks, chemical and biological registration, screening data management, SAR analysis, reporting, and visualisation. Dotmatics solutions are available for local or cloud deployment and they are supported on Microsoft Windows, Mac OS X and Linux.  A privately owned company, Dotmatics was founded in 2005 and their headquarters is based south of Cambridge in the UK. C4XD is a Manchester-based company focused on optimising drug discovery and design. It was founded in 2008 as a spin-out from the University of Manchester. The company uses its NMR-based technology to solve the dynamic 3D structures of a broad range of biomolecules, including peptides, cofactors, oligonucleotides and carbohydrates. Since C4XD's NMR technology shows what shapes active molecules prefer to adopt, it provides high-quality templates for drug discovery and design, and valuable information for drug candidate optimisation. In addition, the data is generated faster and more reliably than standard techniques such as X-ray co-crystallography or molecular modelling. C4XD is using its technology in collaboration with the pharmaceutical industry and to build its own proprietary pipeline of high-value therapeutic candidates. For additional information please go to http://www.c4xdiscovery.com

C4X Discovery | Entity website

The Company was admitted to AIM on 23 October 2014. The Directors acknowledge the importance of the principles set out in the Corporate Governance Code ...

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