CANCER DRUG DISCOVERY
Prof Clive Williams
Clive Williams, BSc, M.A., PhD
Professor of Chemical Biology
Fellow of Trinity College
Member of The Royal Irish Academy
Dean, Faculty of Engineering, Mathematics and Science
Research, Teaching and Dean:
Email for all business: email@example.com
Room 6.05 Biomedical Sciences Institute;
Research Group Lab 6.14
Biomedical Sciences Institute
Dean: Faculty Office, Hamilton Concourse College
Current Research Interests and Projects
Areas of Research:
- Protein Structure-Function Relationships
- Cancer Drug Discovery
- Characterisation of a new class of apoptotic agents in collaboration with Dr Daniela Zisterer.
PBOX compounds (pyrrolo-1,5-benzoxazepines) have shown utility in in vitro, ex vivo and in vivo models of various cancers. Many of these compounds target tubulin as microtubule disruptors, whereas others have anti-proliferative activity through an unknown target. Over 20 papers have been published together with patent protection of these compounds and these compounds are also being studied in several other laboratories including those of Lawlor (TCD), Hollywood (TCD), Kelleher (TCD), and McGee (UCD). A collaborative project with David Lloyd seeks to produce compounds based on new scaffolds which mimic the tubulin-targetting activity of PBOX compounds.
- In silico drug design in collaboration with Dr David Lloyd.
Various projects are in progress including the scaffold-hopping PBOX project described above, as well as steroid receptor, hexokinase/Warburg effect inhibitors, and SMAC-mimetic IAP inhibitors. (published papers)
- Characterisation and development of photo-activatable compounds for use as therapeutics and imaging agents with Prof Thorri Gunnlaugsson.
The rational design of new anti-cancer agents has been greatly aided by rapid advances in genome and cellular research and this gives academic interdisciplinary research groups the ability to bring forward new targets and agents based on such research. Such research provides for innovative, cutting-edge training in research at a PhD level. This project studies the potential of newly synthesised photo-activatable compounds based on Ru-II polypyridyl complexes and higher order complexes with nanoparticles to kill cancer cells, to provide information on potencies and mechanisms to allow the design of more potent and selective compounds which through further biochemical studies can provide a chemical series of compounds which have chemotherapeutic potential and thus can be protected and further advanced through the drug development pathway. The studies include in vitro, ex vivo, imaging, animal model and molecular modelling approaches. Preliminary studies in our laboratories have shown activity of some of these compounds towards lymphoma and lung cancer lines.
Characterisation of Perinuclear Clustering of Mitochondria in Cellular Homeostatis and/or cell death.
In collaboration with Prof Thorri Gunnlaugsson and Dr Derek Nolan
- Characterisation of amphetamine compounds as anticancer agents with Prof Mary Meegan
Novel and existing amphetamines are being investigated for an ‘alternative use' activity, viz, induction of programmed cell death as a novel mechanistic route for cancer therapy. The mechanism does not involve the monoamine transporter known targets for amphetamines. Their utility as cancer therapeutics is being investigated at an in vitro level in drug resistant cancer cell types. (published papers)
- Characterisation of antidepressants as agents inducing programmed cell death.
Novel and existing antidepressants are being investigated for an ‘alternative use' activity, viz, induction of programmed cell death as a novel mechanistic route for cancer therapy. The mechanism does not involve the monoamine transporter known targets for uptake-inhibitor-based antidepressants. Their utility as cancer therapeutics is being investigated at an in vitro level in drug resistant cancer cell types. (published papers)
- Characterization of the interactions of antidepressants and related compounds with Toll Receptors and the role in innate immunity and its dysregulation with Prof Luke O'Neill
Some antidepressants and related molecules can inhibit Toll receptors and so they and novel structural analogues may have potential in various syndromes in which Toll receptors play a role. Studies are in progress to investigate these phenomena at an in vitro level.
Current Research Group Members
Dr Sandra Bright
Dr Trevor Price
Ms Luisa Erby
Ms Kim Orange
Dr Trevor Price on his PhD graduation day with other members of the Williams
Dr Sandra Bright, Ms Kim Orange and Ms Luisa Erby
Congratulations to Trevor Price on his successful PhD viva - April 2012
New Research Highlights Live Cancer Cells Using Glowing Nanoparticles
New collaborative research by scientists at Trinity College Dublin has resulted in the development of a new approach to visualising live cancerous cells using luminescent metal based nanotechnology. Led by Professor in Chemistry, Thorfinnur Gunnlaugsson and Professor of Biochemistry, Clive Williams, the research forms part of a collaborative effort between the School of Chemistry and the School of Biochemistry and Immunology to develop novel delivery methods and alternative approaches to cancer therapies. The research article was published recently in the Journal of the American Chemical Society and represents the first piece of published research from the new Trinity Biomedical Sciences Institute.
Ruthenium (II) polypyridyl complexes are a class of compounds that display rich photophysics and photochemistry. The research paper investigates the synthesis of Ru(II)-polypyridyl stabilised, luminescent gold nanoparticles (AuNPs). These structures bind to DNA with some enhancement in their luminescent properties and undergo rapid cellular uptake, being localised within the cell cytoplasm and nucleus within a few hours. These findings could lead to advances in current cancer diagnostic and treatment efforts and will form the basis of a project that will look to exploit the advantageous properties of such gold-ruthenium based nano-systems for understanding cellular function and behaviour.
Authors of the study, Kim Orange, Professor Clive Williams, Dr Rob Elmes and Professor Thorfinnur Gunnlaugsson .
Speaking about the research, Professor Thorfinnur Gunnlaugsson said: “This research provides a proof of principle but we now need to progress this project further. We have the synthetic and spectroscopic expertise in the School of Chemistry as well as within the infrastructure of Trinity's nanoscience institute, CRANN , which allows us to modify and tune the properties of such nanoparticle systems. While within the School of Biochemistry and Immunology we have the instrumentation and experience to evaluate their potential in various biological applications. By simply changing their outer shell, these gold–ruthenium nano-conjugates should provide advances in areas such as fluorescent biomarkers, drug delivery systems and also in photo-activated cancer therapies.”
Commenting on how this multidisciplinary approach to research can bring about new advances and added benefits for future applications of such technologies, Professor Clive Williams said: “The completion of the Trinity Biomedical Sciences Institute allows for more facile delivery of such quality pharmaceutical and biotechnological research. This collaboration has already resulted in our research being published in internationally renowned scientific journals and with both research groups now being housed in one purpose built facility we hope that collaborations of this nature will become more commonplace here at Trinity College.”
The full research paper, entitled ‘Luminescent Ruthenium(II) Polypyridyl Functionalized Gold Nanoparticles: Their DNA Binding Abilities and Application As Cellular Imaging Agents', can be viewed online.
Senior Sophister Project student, Kim Orange wins Best Poster Prize for Biochemistry and Structural Biology
Kim together with Clive Williams, Suzanne Cloonan and Trevor Price
Current Commercial Interactions
Clive Williams is a founder of Codex Discovery Ltd. and Codex Oncology Ltd., Trinity College campus companies.
Health Research Board of Ireland, Enterprise Ireland, Science Foundation Ireland, EU DGXII R & D programmes, Industry.
Current Research Collaborations
Dr Daniela Zisterer, School of Biochemistry and Immunology, Trinity College, Dublin, Ireland
Dr David Lloyd, School of Biochemistry and Immunology, Trinity College, Dublin, Ireland
Prof Mary Meegan, School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin, Ireland
Prof Thorri Gunnlaugsson, School of Chemistry, Trinity College, Dublin, Ireland
Prof Mark Lawlor, School of Medicine, Trinity College, Dublin, Ireland
Prof Luke O'Neill, School of Biochemistry and Immunology, Trinity College, Dublin, Ireland
Dr Derek Nolan, School of Biochemistry and Immunology, Trinity College, Dublin, Ireland
Dr Suzanne Cloonan, Pulmonary and Critical Care Medicine, Harvard Med School, Brigham and Women's Hospital
Recent Publications by the Cancer Drug Discovery Group
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