Winner: 2024 Chemistry Biology Interface mid-career Prize: Jeremy Knowles Award
Professor Angela Russell
University of Oxford
For innovation in medicinal chemistry leading to the identification of first in class utrophin modulators for the treatment of Duchenne muscular dystrophy.
Professor Russell鈥檚 work seeks to develop an effective drug to treat children with the fatal muscle-wasting disease Duchenne muscular dystrophy (DMD) by increasing the levels of a muscle protein called utrophin. Utrophin is a protein related to dystrophin, the protein that is absent in DMD. It has the potential to act as a substitute for dystrophin and restore muscle function in patients. Ezutromid was developed from work in Professor Russell鈥檚 labs and is the first drug designed to treat DMD by increasing the amount of utrophin in muscle cells. Summit Therapeutics began a clinical trial to test whether ezutromid would be a beneficial treatment for children with DMD. The clinical trial showed promising results after 24 weeks of treatment. However, the drug wasn鈥檛 effective over a longer period, and in 2018, Summit discontinued its development. As a result, Professor Russell鈥檚 group investigated how ezutromid works to uncover new opportunities for alternative drugs that might act in a similar yet more effective way. They demonstrated that ezutromid binds to a protein called the aryl hydrocarbon receptor (AHR), leading to more utrophin production. The group have found new alternative molecules that bind to the AHR and increase utrophin production, which overcomes the problems with ezutromid. They are currently trying to develop these new molecules into a new drug to give lasting benefits to all patients with DMD.
Biography
Angela Russell gained her DPhil in organic chemistry in 2004 under the joint supervision of Steve Davies and Tim Perera from Yamanouchi plc (now Astellas Pharma Inc.). In 2007, she was awarded a prestigious Research Council UK Fellowship in Medicinal Chemistry. In 2012, she became an Associate Professor, and in 2018, she was promoted to Professor of Medicinal Chemistry, a position she holds jointly between the Departments of Chemistry and Pharmacology at the University of Oxford. Her research concerns the discovery and translation of new molecules and mechanisms to manipulate cell fate, particularly for degenerative diseases. To achieve this, she has realised several successful multidisciplinary research collaborations, including identifying small molecules to upregulate utrophin for the treatment of Duchenne muscular dystrophy (DMD) and developing novel inhibitors and activators of developmental signalling pathways and new anti-cancer agents. Angela has published over 130 original articles, book chapters and patent applications. She has founded three companies: MuOx Ltd in 2012 (acquired by Summit Therapeutics plc), Oxstem Ltd in 2016 and Kodiform Therapeutics Ltd in 2024 to translate her research towards new treatments. She has also been involved in taking two products to clinical trial, one in DMD and the other in COVID-19. In 2016, Angela was named a 鈥楻ising Star鈥� in the 鈥楤ioBeat 50 Movers and Shakers in BioBusiness 2016鈥� report. Released annually, the report celebrates 50 outstanding women entrepreneurs and business leaders who are recognised for their contributions to global health innovation. In 2020, she received a Harrington Rare Diseases scholarship award in recognition of her pioneering work to develop a therapy for DMD.
Q&A with Professor Angela Russell
How did you first become interested in chemistry?
I鈥檝e always been driven by a desire to carry out research for the betterment of human health. Chemistry was a subject I absolutely loved at school and saw as fundamental to all science because it underpins and impacts so many other disciplines, including medicine.
Tell us about somebody who has inspired or mentored you in your career.
There are several important people to me in my career journey, and I believe good and compassionate mentorship is often key to success. My dad was always supportive of my ambitions. He was a trained scientist himself, but early in his career decided to move to work in a bank. From a very early age, he inspired me with a love of science, and when I was 14, I recall him telling me 鈥榊ou鈥檒l never be happy with a desk job鈥�. He was absolutely right.
I also had an inspirational chemistry teacher while I was at high school.
He was the first person I ever met with a doctorate in science and I was fascinated to hear about his research experience. These conversations were important in making me realise that I might have many of the qualities it takes to become a successful scientist, including a natural curiosity, logic, and a determination to succeed.
Two main people have been critical to my success and hugely influential on my career trajectory: Steve Davies, my PhD supervisor and Dame Kay Davies, my long-term collaborator in DMD, both of whom have been long-term mentors to me.
Both are extraordinarily successful scientists, but Steve, in particular, is also an extremely successful entrepreneur, and Kay as a strong role model for a successful female leader in science.
What advice would you give to a young person considering a career in chemistry?
I would encourage them to pursue their dreams: it's an incredibly exciting time to start a career in chemistry with so many opportunities to positively impact on health and the environment. I believe the decisions that you make at the beginning of your career are important and can impact your whole future, so I would encourage a young person to think long-term wherever possible. Everyone makes mistakes, but recognising when you aren鈥檛 on the right track and correcting it quickly makes it easier to stay on course. I originally came to university to study biochemistry, but realised quickly that it wasn鈥檛 right for me. Two weeks before my first-year exams I told my tutor I wanted to change to chemistry. I flipped straight into the second year of a Chemistry degree and almost gave my tutor a heart attack, but it was exactly the right decision for me at that time.
I would also encourage a young person to not be afraid of failure: I believe this mindset is key to being bold and pursing the most innovative and transformative ideas.
What has been a challenge for you (either personally or in your career)?
The biggest highlight and the biggest challenge in my career have come during our 20+ year pursuit for a treatment for Duchenne muscular dystrophy. I was involved from the earliest stages to establish proof of concept that a small molecule could be developed to switch on the production of utrophin in muscle to treat the disease, despite the scepticism towards the approach early on. The biggest challenge in my career came following the clinical trial of the drug arising from our work, ezutromid failed to show sustained efficacy in patients with the disease. This was a devastating outcome for everyone involved, and most of all, for the patients and their families who had their hopes dashed. It also led to the loss of all our funding streams for the programme.
However, with this backdrop, instead of giving up, we chose to try to understand the reasons why the drug failed in the hope that we might be able to develop a new drug to surmount the problems of ezutromid.
By applying chemistry we were able to understand the mechanism of ezutromid and why it did not give a lasting benefit in patients. These findings have allowed us to develop a new generation of molecules that overcome the issues of ezutromid, which we are currently progressing towards the clinic.