How did you get interested in Chemical Biology?

I got fascinated about chemical biology when realizing that (i) we don’t know the molecular mechanism of action of many approved drugs and (ii) many drugs are non-selective and, in fact, block different proteins and associated pathways. To me, this was absolutely stunning.

What was the topic of your PhD project? Where and when did you obtain your PhD diploma?

I conducted my PhD studies at CeMM under the supervision of Prof. Giulio Superti-Furga, mostly focusing on chemical proteomics, functional genomics as well as drug combination studies to understand the mechanism of action of anti-cancer drugs. For my postdoc, I worked with Jay Bradner at the Dana Farber Cancer institute. This is when I fell in love with the paradigm of targeted protein degradation.

Where are you currently working and what is your current position?

I am currently a principal investigator at CeMM where I lead a multi-disciplinary research team of 12 scientists working in chemistry, molecular biology, and bioinformatics.

What are your current research interests?

We are excited about the concept of “chemical neomorphs” or, in other words, small molecules that allow us to endow a target protein with a novel function. This includes target protein degradation via PROTACS and molecular glues where we functionally reprogram E3 ubiquitin ligases to induce the degradation of disease-relevant proteins. But increasingly, it also goes beyond that.

What kind of tasks does your work involve?

Unfortunately, I don’t find the time to do experiments anymore. Hence, most of my tasks are around communicating, brainstorming, and organizing our research. Thinking about a scientific problem and discussing it with my students and postdocs is what I like best. Of course, it also includes presentations at meetings and conferences, and writing research grants.

How many PhD students and postdocs do you currently supervise? Are you currently looking for a new PhD student or a postdoc?

7 postdocs and 4 students. We are always excited for curious and courageous people that want to work in our team.

How would you describe yourself as a supervisor?

I think I am very approachable and easy to excite and, hopefully, empathic. However, I think I am also somewhat demanding but try to ignite intrinsic motivation rather than applying external pressure.

What are the features of a successful PhD student or postdoc?

You need to love what you are doing, and you need to constantly check if you are asking the right/most interesting questions. Talk to your peers. Get them excited. Don’t be afraid to cross scientific boundaries and involve different disciplines. Dream big and be resilient.

What do you consider your greatest achievement in your scientific career?

My postdoctoral work (Winter, Buckley et al. Science 2015) where we could show, for the first time, in vivo degradation of a protein via an all-chemical degrader is probably the most influential work (>1200 citations).

Which of your papers are you most proud of and why?

Among others, the following come to mind:

• A 2014 Nat Chem Bio paper where we elucidate the MoA of the anti-cancer compound YM155
• A 2017 Nature paper where we have developed a degron technology to validate ENL as a target in acute leukemia
• A 2020 Nature Genetics paper where we use the same degron technology to systematically dissect a transcriptional coactivator complex
• A 2020 Nat Chem Bio paper where we describe a rational approach to identify molecular glue degraders
• A 2023 Nat Chem Bio paper where we describe resistance mechanisms to small-molecule degraders

What is the most embarrassing thing you have done in the lab while doing experiments, e.g. explosions?

I once ordered a large flask of ethanethiol and opened it outside the fume hood. We had to evacuate the lab due to the horrific smell.

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

I enjoyed reading “Empire of Pain”, telling the shocking story of the Sackler family, Purdue Pharma and OxyContin. I also loved “For Blood and Money”, a book that details the fascinating development of the clinically highly successful BTK inhibitors.

What would you expect to be the next major breakthrough in medicinal chemistry?

Proximity-inducing small molecules. I am convinced that targeted protein degradation is just chapter one. We will find more and more strategies to rationally rewire biological circuits and I think we will witness a convergence of chemical biology and synthetic biology. Of course, aspects of that will be critically empowered by artificial intelligence and machine learning.

Keynote talks from Ben Davis (Oxford), Ivan Dikic (Frankfurt) and Teresa Carlomagno (Birmingham) highlighted the topic ‘From Biological Mechanisms to Novel Drug Targets’. The latest research in chemical biology was presented by Stuart Conway (UCLA) and Christa Müller (Bonn).

On the second day, the hot topic ‘Artificial Intelligence in Drug Discovery’ was discussed by Matthias Rarey (Hamburg) and Ole Engkvist (Gothenburg). The importance of synthesis was underlined in the last session entitled ‘Chemistry-driven Drug Innovation’ with talks from Erick Carreira (ETH Zürich), Eric Fischer (Dana Farber, Boston), and Masatoshi Hagiwara (Kyoto University).

Beyond the keynotes, 16 additional talks and a session with 77 posters gave an overview on latest results in drug discovery. In addition, two workshops on ‘drug-repurposing‘ and ‘3D Modeling for the non-savvy” were organized by Fraunhofer ITMP and BioSolveIT, respectively.

The conference was accompanied by an industry exhibition and supported by 15 sponsors (platinum sponsor: Roche).  

The HDDC proved to be an excellent format to discuss the challenges and chances of modern drug discovery in academia and industry and Helmholtz Health Researchers plan continuing the series in the future.