How did you get interested in Medicinal Chemistry?

I obtained my master’s degree in pharmacy at National and Kapodistrian University of Athens. During my studies, I was fascinated by the fact, that a small chemical compound can target the underlying mechanisms of a disease and restore the balance in the complex cellular environment. Drug design seemed like a form of art to me. I also loved both organic chemistry and pharmacology, so I realized that medicinal chemistry was the perfect place for me. I could work in the interface of different disciplines and contribute to the discovery of a drug that could help patients. 

So, then I decided to pursue a PhD in medicinal chemistry with my mentors Prof. Nicole Pouli, Prof. Panagiotis Marakos and Prof. Emmanuel Mikros at University of Athens. I worked on the discovery of novel substituted purine isosters as anti-cancer agents, focusing on kinase inhibitors. In addition, I worked on a separate project for the development of chemical tools to study fungal nucleobase transporters. During my PhD, I developed synthetic skills, especially for heterocyclic compounds and learned the principles of drug discovery.

Where did you have your postdoc position?

After finishing my PhD, I decided to move abroad for my postdoc, in order to broaden my horizons and obtain new skills. In 2019, I joined Prof. Caroline Springer’s group at the Drug Discovery Unit of Cancer Research UK Manchester Institute. I loved being in a multidisciplinary environment, surrounded by experienced scientists in all aspects of drug discovery. In this ‘industrial-like’ setting, I gained expertise in all stages of a modern campaign, from hit generation, to lead identification and optimization. I worked on two kinase inhibition projects for oncology indications, with the prospect of nominating a clinical candidate, and I experienced all the challenges that a medicinal chemist faces, when trying to optimize the overall profile of a series.

Where are you currently working and what are your current research interests?

After my three-year postdoc at Cancer Research UK Manchester Institute, I moved in 2022 to Imperial College London to become a Research Associate in Prof. Ed Tate’s group. I have been leading the medicinal chemistry part of several projects in the areas of oncology, immunology and neglected tropical diseases. We design and synthesize probes that help us study new targets using activity-based protein profiling (ABPP) and we optimize library screening hits to discover potent and selective compounds with suitable pharmacokinetic properties for in vivo evaluation. Furthermore, we focus on advancing the field of targeted protein degradation or stabilization, both by developing new PROTACs and DUBTACs against established targets, and by discovering new ligands for E3 ligases and deubiquitinases.

What do you like best about your work and how many students do you currently supervise?

Our group has over 60 members working across different, but overlapping scientific fields. I enjoy being next to people, who specialize in chemical biology and proteomics, as each one of us possesses distinct skills, and through our collaboration, we can achieve the successful completion of a project. In addition to performing ‘hands-on’ work in the lab, I am currently supervising a group of about 10 students (PhD, Master, undergraduate), which gives me the opportunity to design projects and transfer my skills to junior scientists. As a supervisor, I like paying attention to experimental details, but also, I encourage my students to take initiative for their projects and become independent. Overall, I would describe the research performed in our group, as a multidisciplinary team effort to unlock new therapeutic targets and open a new pathway for the treatment of devastating diseases.

What is your greatest achievement in your scientific career?

The Hedgehog signalling pathway is aberrantly activated in many types of cancer and in fibrotic diseases. Although inhibitors of Hedgehog signalling that target the Smoothened (SMO) protein have been approved, they are not effective in all cases, so there is an urgent need for an alternative strategy. In the Tate group at Imperial, we have discovered the most potent and the first orally bioavailable inhibitors of Hedgehog Acyltransferase (HHAT) as a novel approach to target the Hedgehog pathway. Our work could expand the therapeutic options for patients suffering from Hedgehog-related diseases. I am grateful to the EFMC for giving me the opportunity to present our research results at the EFMC-ACSMEDI Medicinal Chemistry Frontiers in Utrecht and at the XXVIII EFMC International Symposium on Medicinal Chemistry in Rome.

What are the features of a successful PhD student or postdoc and how would you advise scientists facing unfair or challenging situations?

Being a researcher is an extremely challenging job, especially in the early stages of our careers. The failures we face frequently in our experiments, combined with the uncertainty regarding our future career development, create significant stress for PhD students and postdocs. However, the feeling of excitement we get after a scientific achievement is unique and gives us the strength to keep going. Passion is key for the successful completion of our scientific tasks.

As researchers we can’t always predict the outcome of our experiments. The pathway to reach the end of our PhD or postdoc is not a straight line. However, we can do our best to rationally design our experiments, by thinking through all the parameters, studying comprehensively related literature and by efficiently managing our available time. Discussing our work with colleagues always helps, and even a casual chat over coffee can generate wonderful ideas. Furthermore, attending conferences and becoming part of a scientific network are extremely valuable, both for our current work and future career. More importantly, I would encourage everyone to express any mental health issues and speak up about the challenges they face. We should all try to create supportive working environments and help each other.

What would you like to ask from other medicinal chemists?

We have to be aware of the limitations of our skills and respect the expertise of others in certain aspects of our projects. For example, we should seek for advice from computational chemists for molecular modelling studies (especially the more complex ones!) and have a good collaboration with the biology team in a drug discovery project. We must evaluate objectively the profile of a compound and its value for the project, without any bias, because sometimes, we might develop an ‘emotional attachment’ towards a compound we designed and synthesized.

What is the most embarrassing thing you have done in the lab while doing experiments?

My first reaction during my Master’s project was nitration of an aminopyridine that leads to two isomers. My supervisors had done this many times and knew exactly the polarity and ratio of the two isomers. However, I saw only one spot in my TLC plate, that always moved all the way up to the solvent front, even with very non-polar eluent systems. After many discussions and digging up old lab notebooks for thorough exploration of this ‘scientific mystery’, I realized that I had mixed the hexane and methanol bottles… :)

What are your recommendations for a book, website, blog or film?

Book: Any of Agatha Christie

Website: Drughunter.com

Blog: ‘In the pipeline’ by Derek Lowe

Films: The Fountain (2006), The Broken Circle Breakdown (2012) and Radioactive (2019) – must watch for chemists and cancer researchers!

Which scientist do you admire the most and why?

I admire scientists, like Rosalind Franklin or Alan Turing, who in different ways and for different reasons, were not respected at their time or their work was not acknowledged. Of course, also pioneers like Marie Sklodowska-Curie and Katherine Johnson, who managed to overcome both gender and racial barriers. Unfortunately, these are just examples of a very long list.

Which field of medicinal chemistry and drug discovery do you consider the most promising for the future and what would you expect to be the next breakthrough?

In recent years we have witnessed achievements that were once considered impossible. Drugs have been approved for targets that were supposed to be undruggable. The land ‘beyond the Ro5’ that once seemed forbidden, is now accessible. New modalities are validated in the clinic and expand our therapeutic toolbox. Especially, in the field of induced proximity, I believe we have only seen a minor fraction of what we can achieve. If we elucidate the role of more E3 ligases and deubiquitinases and recruit them; if we rationalize the discovery of molecular glues, not just for degradation; if we can design ligands for any binding pocket in proteins-of-interest, no matter how shallow or ‘unfriendly’ it looks, then we can rewire the cellular networks and restore the disrupted balance. The rise of AI/ML and new automation technologies can significantly alter drug discovery, as we know it. But are technological breakthroughs alone, sufficient to lead to drug discovery breakthroughs? Despite the current hype, I believe the answer is ‘no’. However, if they are used sensibly and are combined with the actual intelligence and experience of scientists, then only sky is the limit for the future of medicinal chemistry and drug discovery.

The Prize has been established by a generous gift from the Chemical Works of Gedeon Richter, Plc.  (Budapest, Hungary) to acknowledge the key role that medicinal chemistry plays toward improving human health.

Applicants should be received by NOMINATION only, with just one person needing to serve in that capacity, although a total of five (5) individuals should be listed as referees overall. The package must be submitted electronically and should contain a complete resume, a professional biography of not more than two pages, and a one-page summary of what the individual considers to be their activities, accomplishments and/or publications that have had the most significant impact upon the field of Medicinal Chemistry. The material will be forwarded confidentially to an independent selection committee appointed by the IUPAC Subcommittee on Medicinal Chemistry and Drug Development.

For further information please contact Prof. Janos Fischer, Member of the IUPAC Sub-committee on Drug Discovery and Development, by email at fischer-ext@gedeonrichter.com

The DPhG already offers a variety of initiatives to support early-career scientists, including an annual PhD and postdoc meeting, prizes for PhD students, mentoring programs, and travel grants for attending the annual DPhG conference. Building on this foundation, the YPS complements and expands support for young scientists through our own targeted projects.

For example, we organize a dedicated session at the annual DPhG meeting, providing four PhD candidates or postdocs the opportunity to deliver an oral presentation on a national stage. Additionally, we invite a session speaker, selected from pre-tenure or recently tenured group leaders, to inspire and engage young attendees. Other initiatives include social get-togethers during DPhG meetings, online workshops focusing on career development and networking, and the creation of a forum designed to foster collaboration and exchange among early-career scientists. More information can be found on the DPhG-website or on our social media channels (LinkedIn and Instagram).

At YPS, we are committed to supporting pharmaceutical early-career researchers in every way possible. We warmly invite all early-career scientists from all pharmaceutical disciplines to join us, contribute their ideas, and help shape the future of pharmaceutical research. We are incredibly excited about what lies ahead!

Targeting RNA with small molecules is an emerging field in medicinal chemistry and chemical biology. However, developing high potency RNA binders can be challenging. In their work, Almena Rodriguez et al. investigated the intuitive strategy to enhance affinity via introduction of positively charged moieties. Using ligand series for the preQ₁ and SAM-VI riboswitch aptamers, they elucidated not only affinity but also selectivity, binding thermodynamics, and kinetics by SPR, ITC and MST.

Their results showed that RNA-ligand binding for these targets is dominated by enthalpy. For RNA-ligand development electrostatic anchors only had moderate effects on binding affinity largely due to slightly enhanced association rates. Despite observing loose binding behavior in SPR with multi-basic ligands, selectivity over structurally unrelated RNA off-targets was maintained.

While the addition of positively charged moieties might not hold up as a universal RNA-ligand design principle, a purposefully implemented ionic RNA-ligand interaction can enhance potency without impairing selectivity.