Cancer Research UK Edinburgh Centre

Edinburgh Cancer Discovery Unit (ECDU)

Driving innovation in oncology drug discovery and development.

ECDU research

The ECDU was founded in 2011 as a not-for-profit activity to provide a multidisciplinary group of core skills embracing advanced technology platforms and disease models, which drive innovations in oncology drug discovery and development.

The overarching aims of the ECDU are to enhance clinical predictivity of preclinical oncology drug discovery strategies and improve patient stratification and efficacy, by applying an evidence-led translational research platform, incorporating disease relevant model systems, innovative chemical design, quantitative imaging and genomic/proteomic discovery informatics. To achieve these goals we work in close collaboration with local clinicians, multidisciplinary academic research groups (biology, chemistry, informatics & biophysics) and industry partners. The ECDU provides a dynamic environment combining, complimentary skills, advanced technologies and clinical research collaborations that address unmet clinical need and thus maximise the value of our preclinical research programs and small-molecule or biological therapeutic assets discovered or profiled through these programs.

ECDU's core capabilities are listed below:

Innovative Small Molecule Synthesis and Medicinal Chemistry

Edinburgh Drug Discovery’s medicinal chemists are experts in small molecule and peptide synthesis. They specialise in ligand-based drug design and strategically combine this with phenotypic screening to produce highly potent, exquisitely selective compounds with a high degree of drug-like characteristics. Our chemists have received acclaim for their design of palladium-activated prodrugs, using biorthogonal chemistry and the rapid development of highly potent and selective targeted inhibitors (selection of recent publications below):

  1. Fraser C, Dawson JC, Dowling R, Houston DR, Munro AF, Muir M, Harrington L, Webster SP, Frame MC, Brunton VG, Patton EE, Carragher NO and Unciti-Broceta A. Rapid Discovery and SAR of Pyrazolopyrimidines that Potently Suppress Breast Cancer Cell Growth via SRC Inhibition with Exceptional Selectivity over ABL J Med Chem. 2016 May 26;59(10):4697-710.
  2. Fraser C, Carragher NO, Unciti-Broceta A. eCF309: a potent, selective and cell-permeable mTOR inhibitor. Med. Chem. Commun., 2016,7, 471-477
  3. Weiss J, Dawson J, Fraser C, Rybski W, Torres-Sanchez C, Bradley M, Patton E, Carragher NO, Unciti-Broceta, A. Development and Bioorthogonal Activation of Palladium-Labile Prodrugs of Gemcitabine. J Med Chem. 2014 Jun 26;57(12):5395-404.
  4. Weiss JT, Dawson JC, Macleod KG, Rybski W, Fraser C, Torres-Sánchez C, Patton EE, Bradley M, Carragher NO, Unciti-Broceta A. Extracellular palladium-catalysed dealkylation of 5-fluoro-1propargyl-uracil as a bioorthogonally activated prodrug approach. Nat Commun.  2014; 5:3277.

Phenotypic Screening

Our research unit is also highly proficient in image-based phenotypic screening, working in close collaboration with several pharmaceutical industry partners and academic groups to identify hit molecules, advance small-molecule lead generation and classify compound mechanism-of-action through multiparametric high content profiling. Our laboratories are equipped with the latest kinetic (IncuCyte Zoom®) and High-content (ImageXpress-micoXL with 3D deconvolution) screening platforms, fully integrated with plate handling robotics, barcode sample tracking and image-analysis/-informatics workflows. We are founding members of the European Cell Based Assay Interest group; www.eucai.org, and together with the Universities of Oxford and Dundee, the third major academic hub for the newly formed U.K. National Phenotypic Screening Centre; www.npsc.ac.uk. We are recognised leaders in the development of high content phenotypic screening technologies (selection of recent publication below):

  1. Warchal SJ, Dawson JC, Carragher NO. Theta-Comparative-Cell-Scoring (TCCS) Method to Quantify Diverse Phenotypic Responses between Distinct Cell Types. Assay Drug Dev. Technol. 2016 Sep;14(7):395-406.
  2. Warchal SJ, Unicti-Broceta A, Carragher NO. Next Generation Phenotypic Screening. Future Med. Chem. 2016. Jun 30. 2016 Jul;8(11):1331-47.
  3. Carragher NO, and Dawson JC. Quantitative phenotypic and pathway profiling guides rational drug combination strategies. Front. Pharmacol. 2014 May 28;5:118.
  4. Ljosa V, Caie P.D., Horst R., Sokolnicki K.L., Cooke, E.L., Daya S, Roberts ME, Jones T.R., Clemons, P.A., Carragher NO, Carpenter A.E. Comparison of methods for image-based profiling of cellular morphological responses to small-molecule treatment. J Biomol Screening. 2013  Dec;18(10):1321-9.
  5. Isherwood BJ. Walls R, Roberts M, Houslay T, Brave S, Barry S, Carragher NO. High-content analysis to leverage a robust phenotypic profiling approach to vascular modulation. J Biomol Screening. 2013 Dec;18(10):1246-59.
  6. Carragher NO, Brunton VG, Frame MC. Combining imaging and pathway profiling: an alternative approach to cancer drug discovery. Drug Discov Today. 2012 Mar;17(5-6):203-14.
  7. Caie PD, Walls RE, Ingleston-Orme A, Daya S, Houslay T, Eagle R, Roberts ME, Carragher NO. High-content phenotypic profiling of drug response signatures across distinct cancer cells. Mol Cancer Ther. 2010 Jun;9(6):1913-26.

Target Validation

We adopt a broad systems pharmacology approach to unbiased identification and validation of novel therapeutic targets. Through integrated clinical informatics and empirical phenotypic profiling across disease-relevant cell model systems we simultaneously explore disease linkage and functional validation of new therapeutic targets.  Our high content imaging and high throughput proteomics platforms combined with precise genetic and pharmacological manipulation in disease relevant model systems provides an in-depth empirical approach to the study of target biology at phenotypic and pathway levels within appropriate physiological and pathophysiological context. The ECDU provide an optimal interface between clinical research, basic research and industry to evaluate new target hypothesis and in-depth investigation of drug mechanism-of-action, biomarker discovery and novel drug combination strategies.

ECDU Directors

The ECDU is jointly directed by four senior scientists that bring together complimentary skills and experience in basic cancer research, pharmacology, drug discovery and imaging gained from within academic and industry environments:

  • Prof Neil Carragher, Principal Investigator Phenotypic Drug Discovery
  • Dr Asier Unciti-Broceta, Principal Investigator Chemistry
  • Prof Val Brunton, Principal Investigator in Cancer Therapeutics and Pharmacology
  • Prof Margaret Frame, Cancer Research UK Edinburgh Centre, Science Director

Contact

n.carragher@ed.ac.uk