Research

Phenotypic drug discovery is seeing a resurgence in popularity but its main disadvantage is that the drug target is unknown which leads to a blind medicinal chemistry campaign and difficulties monitoring clinical success. Thus, target deconvolution is of increasing significance as a means of improving attrition in the drug discovery process. My research has aimed to identify the targets of the small molecule ezutromid for the treatment of Duchenne Muscular Dystrophy. Duchenne muscular dystrophy (DMD) is an X-linked muscle wasting disease which affects about 1 in 5000 boys. DMD leads to loss of ambulation and reduction of average life expectancy to the late 20s, and there is currently no cure. It is caused by loss of dystrophin protein, from one of hundreds of different dystrophin gene mutations.

Ezutromid and a comparison between dystrophin and utrophin

One therapeutic strategy aims to increase levels of utrophin, a natural paralogue of dystrophin. Increasing utrophin rescues the dystrophic phenotype in disease model mice and offers a potential therapy which is independent of DMD patient mutation type. Ezutromid is a utrophin modulator, discovered by phenotypic screening, and progressed to a Phase 2 clinical trial in DMD patients (Summit Therapeutics plc). Interim 24-week data excitingly demonstrated reduced muscle fibre damage and increased levels of utrophin, providing the first evidence of ezutromid target engagement and proof of mechanism. However, these effects were not seen after the full 48 weeks of the trial. My work aims to define the mechanism of ezutromid in order to help understand the trial results, and to aid development of new generations of utrophin modulators.


Schematic for target identification process
  • January - March 2020

    MRC DTP Doctoral Prize Fellowship

    Russell and Milne labs/OxStem Oncology
    Molecular mechanism discovery for small molecule inducers of myeloblast differentiation for AML

  • October - December 2019

    Science Policy internship, The Royal Society, UKRI funded

    Worked for the International Commission on the Clinical Use of Human Germline Genome Editing

  • October 2015 - October 2019

    DPhil, Systems Approaches to Biomedical Science CDT
    University of Oxford

    Russell lab
    Elucidation of the mechanism of action of utrophin modulators for the treatment of Duchenne Muscular Dystrophy

  • July 2016 to October 2016

    Research placement

    Conway lab
    In silico and in vitro studies towards identification of chemical probes targeting BPTF BRD and PHD2 domains.

  • October 2014 to Jun 2015

    MSci Research project, University of Cambridge

    Paterson lab
    Investigation of novel desymmetrising aldol reactions on meso-dialdehydes

  • June 2014 to September 2014

    Research placement, University of Southampton

    Harrowven lab
    Preparation of precursors for the Total Synthesis of RP-66453 (natural product).

  • June 2013 to August 2013

    Amgen Scholars Program, University of Cambridge

    Gurdon Institute, Miska lab
    Investigating antiviral immunity in C. elegans by forward genetic screen.

  • Easter and September 2013

    Biochemical Society summer vacation studentship, Portsmouth University

    Callaghan lab
    Characterisation of sites on the E. coli small non-coding RNA MicA involved in Hfq chaperone binding.

  • October 2015 to present

    DPhil SABS EPSRC MRC CDT

    Department of Chemistry, University of Oxford
    Pembroke College

  • October 2011 to 2015

    Natural Sciences BA Hons and MSci, First Class

    University of Cambridge, Christ's College
    Specialising in Chemistry, further modules taken in Biochemistry, Cell Biology and Physiology

Research Skills

Organic synthesis:

Design and synthesis of chemical probes with photoaffinity (diazirine) and biotin tags, Structure activity relationship studies, stereoselective synthesis, mg to multi gram scale
Biochemistry: Affinity chromatography for target ID, CETSA, Western blot, RT-qPCR, enzyme inhibition assays, luciferase reporter assays, thermal shift assays, protein purification, cloning
Proteomics: Sample preparation, LC-MS/MS submission, data analysis (Maxquant)
Structural Biology: Protein crystallisation, structure solution by molecular replacement
Cell biology: Tissue culture, microscopy
Computing: Python, Bash, Linux, SciPy, Autodock, LaTeX, Web development (HTML, CSS, Javascript)

Publications and Presentations

Isabel V. L. Wilkinson et al. Chemical Proteomics and Phenotypic Profiling Identifies the Aryl Hydrocarbon Receptor as a Molecular Target of the Utrophin Modulator Ezutromid, Angewandte Chemie, Nov 2019.
Isabel V. L. Wilkinson et al. Characterisation of utrophin modulator SMT C1100 as a non-competitive inhibitor of firefly luciferase, Bioorganic chemistry, Oct 2019.
Maria Chatzopoulou et al. (alphabetical author order including Isabel V. L. Wilkinson) Isolation, Structural Identification, Synthesis, and Pharmacological Profiling of 1,2-trans-Dihydro-1,2-diol Metabolites of the Utrophin Modulator Ezutromid, J. Med. Chem., Oct 2019.
Oral Presentation, Spring 2019 ACS National Meeting, Orlando (2019).
Oral Presentation, ABPP 2019 - Target Discovery and Visualisation using chemical probes, Leuven, Belgium (2019).
STEM for Britain 2019, House of Commons poster presentation, March 2019

Teaching

Teaching the Organic Chemistry course examined in the First Public Examination to Biochemistry undergraduate students.

Demonstrator, Doctoral Training Centre, University of Oxford Introduction to Programming and Drug Discovery modules, which are intensive two-week courses to introduce interdisciplinary students to unfamiliar fields.

Prizes and Scholarships

2018

Pfizer symposium poster prize
2015-2019 Pembroke College graduate scholarship
2014 Sir Ian MacFarlane prize for Excellence (£1000) and the Todd Prize (Christ's College)
2013 Grieg Prize for Natural Science (Christ's College)

Extracurricular Interests

Outreach

STEM Ambassador and six years of volunteering with both Oxford and Cambridge Hands-on Science, bringing small scale scientific demonstrations to schools and the public around the country.
Successful application to the Royal Society of Chemistry Outreach Fund 2018 (£2000)
Enterprise Medicinal Chemistry lead for the start-up Spherox, participated in the 2018 PanaceaStars accelerator and bootcamp.
Badminton 2016-2017 Captain of the Pembroke College badminton team.
2010-2011 Captain of the Christ's College women's badminton team.
Languages Mandarin Chinese and intermediate German
Not for profit Fundraising Officer then Treasurer for Save the Children university society 2012-2014, winning a prize in the Save the Children ultimate uni challenge.