How did you get interested in Medicinal Chemistry?

When I was in high school, I read “The Periodic Table”, a short story collection by the Italian chemist, partisan, writer, and Jewish Holocaust survivor Primo Levi, named after the periodic table in chemistry. Among the others a passage in the short story “Iron” caught my attention and fascinated me: “the nobility of man, acquired in a hundred centuries of trial and error, lay in making himself the conqueror of matter, and that I had enrolled in chemistry because I wanted to remain faithful to this nobility. That conquering matter is to understand it, and understanding matter is necessary to understanding the universe and ourselves: and that therefore Mendeleev's Periodic Table, which just during those weeks we were laboriously learning to unravel, was poetry, loftier and more solemn than all the poetry we had swallowed down in liceo; and come to think of it, it even rhymed!”. In that moment I decided that chemistry should be my own path. Within this context, medicinal chemistry was a natural choice because I have always been fascinated by the chemistry and biology interface, in particular the capability to affect human diseases. To me, medicinal chemistry gives you superpowers!

Where and when did you obtain your PhD diploma?

It was back in 1997, at the University of Rome “La Sapienza”, under the supervision of prof. Marino Artico. My PhD project was focused on the development of 2-alkoxy- and 2-alkylthio-6-arylmethyl-4-oxopyrimidines as a new class of potent non-nucleoside HIV-1 Reverse Transcriptase inhibitors. After the PhD, I spent postdoctoral stints at the Drug Chemistry Center of Italian National Research Center (Rome, 1 year), Italian National Institute of Health (2 years), University of Rome "La Sapienza" (1 year), University of Siena (1 year) before joining the Department of Pharmacy of the University of Salerno, Italy, as an assistant professor. Three years later, I spent a sabbatical period (1 year) as a visiting professor at the Department of Chemistry and Biochemistry of the University of California Los Angeles (UCLA), in the group of Michael E. Jung.

What are your current research interests?

The main interest of my research group (Epigenetic Med Chem Lab, EMCL) is the development of chemical probes for the study of protein targets responsible (directly or indirectly) of epigenetic modifications (KATs, KMTs, DNMTs, PRMTs, KDMs, bromodomain, MBT, Tudor) or of proteins regulated by epigenetic processes (e.g., LINE-1 RT), taking advantage of a multidisciplinary approach combining synthetic organic chemistry, medicinal chemistry, chemical biology, biochemistry and biophysics. But, of course, we also have running projects on other topics outside the epigenetics field.

How would you explain what your research area is to non-scientists?

There are quite a lot of beautiful examples that can be used to better explain epigenetics. In general, I use a musical metaphor. DNA is often considered as if it’s a template, like a mold for a car part in a factory, popping out thousands of identical car parts unless something goes wrong in the process. But DNA isn’t really like that. It is more like a musical score, that could be played in quite different ways like, for example, are the interpretations of “What a wonderful world” by Louis Armstrong and Joey Ramone. And how the DNA score is played depends on epigenetic mechanisms. In my group, we develop chemical tools for studying such mechanisms.

What do you like best about your work?

The freedom to work on what interests me most, coming up with new research ideas, designing experiments and potential molecules, working with intelligent and enthusiastic early career researchers who are willing to embrace exciting new approaches, mentoring students. And I really love the multidisciplinary nature of our research. 

What kind of tasks does your work involve?

It’s been several years since I worked in the lab and it’s a pity as it was the real fun. My current tasks include teaching, writing papers, and finding money for research by writing national and international grant applications. Mentoring PhD students and postdocs and guide them towards the research goals is another important task. And (unfortunately) administrative/institutional tasks also occupy a large part of my time, much larger than I wish.

In science being a good communicator is of high importance, not just for teaching. Curiosity is an essential skill but knowledge, creativity (with the ability to repeatedly generate good ideas), critical thinking (and seeing underlying principles behind data sets and deriving new concepts and principles from them), commitment, persistence, social, communication, and team leader skills as well as intuition are also quite important. 

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

My research group has shrunk a little bit during the last few years because of the COVID19 pandemic. Currently it consists of around 20 people (including assistant and associate professors) and there are 4 PhD students and 3 postdocs, besides many undergraduate students. The group will expand again in the future and applications by talented and motivated candidates with the right background and passion are always welcome.

How would you describe yourself as a supervisor?

I care about the progress of my students and try to push them as much as I can for success. I encourage them to think independently. Good science needs the air of freedom to explore ideas and to be creative, and I give my students and postdocs the required room. I believe that a student that knows the bigger picture is more motivated to accomplish her/his goals and therefore I constantly share with my students the primary goals and future directions so they could choose where to take their projects to.

The social atmosphere in the group is also of high importance.

Supervising students goes beyond providing scientific guidance. Mentoring is crucial for career development, and I always try to encourage and motivate students at a personal level when problems arise during their projects.

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

It is difficult to name one, because I’m very proud of all the research work we have done. Probably one of the most important achievements was the discovery of the first inhibitor of the Tudor-domain-containing protein Spindlin1 (SPIN1), capable of engaging the protein in cells, blocking its ability to 'read' H3K4me3 marks and inhibiting its transcriptional-coactivator activity. Other important ones are the development of an inhibitor of the retrotransposon LINE1 reverse transcriptase which also induces apoptosis in a cell-density-dependent manner and antagonizes tumour growth in animal models, the development of a positive modulator of the lysine acetyltransferase PCAF able to selectively regulate the extinction of conditioned fear, the identification of a novel selective and cell-active chemotype for G9a/GLP inhibitors, based on the underinvestigated 2-alkyl-5-amino- and 2-aryl-5-amino-substituted 3H-benzo[e][1,4]diazepine scaffold, the identification of an allosteric inhibitor of the acetyltransferase p300, and the identification of the first potent PRMT7/9 inhibitor.

But I am also very proud of the career achievements of my former graduate and PhD students, both in academia and industry all over Europe.

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

Curiosity and motivation to learn new topics and techniques together with being passionate about the research project (and science in general) are certainly the most important, even more than having an outstanding knowledge of organic and medicinal chemistry. But do not misunderstand me: cutting-edge research is highly challenging and a strong science education with well-developed laboratory skills is necessary to start tackling significant challenges. Also, I would be lying if I didn’t say that being hard-working is a crucial feature, as well as having a critical mindset and being perseverant and not giving up when things do not work (the first, second, and even a third time). Remaining up-to-date by reading literature, going to conferences, and talking to people are also important together with team spirit, collaboration and good communication skills.

What advice would you give to someone who wants to know more about your field? 

I am pretty sure that most (if not any) medicinal chemists/chemical biologists, both in academia and industry, are happy to discuss science and career development. Personally, I am. So, reach out to anyone who can tell you more about medicinal chemistry/chemical biology and don’t be afraid to ask. There are no silly questions.

It is critical to always be open-minded, combining the deep experience in the field with a global scientific perspective and never hesitate to embrace new developments and new fields. And I would love if academia and industry could work together to train the next generation of medicinal chemists.

Have you experienced any unfair situations during your scientific career? How would you advise scientists facing similar situations?

I guess that anyone has perceived something unfair in her/his own career, for instance reviews of papers and/or grant applications or by company-internal Boards, and I’m not an exception to this. Of course, they are annoying, but in my experience not being too annoyed and trying to take such situations easy helps. I try not to think about the things I didn’t get (and why) and focus and appreciate the things I accomplished

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

There are two episodes, both dated back to my period as an undergraduate student and both related to the use of a rotavap. In the first, I forgot to use the metal (or Keck) clip to secure the flask and before reaching the required vacuum, the flask (a 1000 ml one) fell into the rotavap bath and filled up with the bath water. I had to extract (and purify again) my compound from the whole volume. In another situation, I did not notice that the glass joint of the neck of the flask was not completely clean. Of course, after the evaporation of the solvent it was stuck on the rotavap and when I forced it to come off it cracked and ripped my thumb open. It needed a six-stiches suture at the hospital, and I still have the scar (32 years later).

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

Chemistry is usually represented as a threat or in a negative way in movies. Nonetheless, in my lessons I often quote some specific movie scenes to let students visualize (or better remind) something: for example, the scene from Pulp Fiction of the intracardiac injection of adrenaline by Vincent Vega (John Travolta) to revive Mia Wallace (Uma Thurman) after her heroin overdose, or the story in Awakenings (from the book of the same name by Oliver Sacks) of the repositioning and off-label usage of L-DOPA by Dr. Malcolm Sayer (Robin Williams) to “awake” Leonard Lowe (Robert De Niro) from encephalitis lethargica. Besides The Periodic Table by Primo Levi (and also all his other books) and Awakenings by Oliver Sacks, another book I would recommend is Perfume by Patrick Süskind, with interesting details about olfactory perceptions, extraction techniques, and the chemistry of making perfumes.

Regarding blogs, everyone working in medicinal chemistry should read Derek Lowe’s ‘In the pipeline’ (https://blogs.sciencemag.org/pipeline/) and Dan Erlanson’s ‘Practical Fragments’ ( http://practicalfragments.blogspot.com/) blogs.

As websites I would recommend Drug hunter (https://drughunter.com/) and Endpoints news (https://endpts.com) and, above all, the EFMC website and YouTube channel, in particular the section related to the slide decks and webinars by the Best Practice in Medicinal Chemistry Working Group (https://www.efmc.info/best-practices). 

Which scientist do you admire the most and why?

There are many of them. In my opinion, Dave Evans was one of the most influential scientists in chemistry, who brought together an incredible collection of researchers and inspired many others (including me). Another fantastic scientist was David C. Allis. Not only he gave an amazing contribution to chromatin biology and epigenetics research, but he was known and loved for being a great mentor and a very lovely person. 

Quite often in my talks and in my lessons, I  quote a sentence by Stuart Schreiber: “There should be no problem with biology driving science unless perhaps you happen to be a chemist!”. And, in fact, he and his way to approach biology from a chemist's perspective are of great inspiration for me (together with K.C. Nicolaou, Stuart Schreiber coined the expression “chemical biology”). And I really admire all the colleagues in academia who succeeded in developing a compound that finally ended to become a FDA/EMA approved drug. Two examples are Roberto Pellicciari and Michael Jung.

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

Induced protein proximity is already a reality and I expect than various drugs deriving from this approach will be approved in the near future. Also, I am pretty sure that besides the few examples already approved, many other therapeutics targeting proteins involved into epigenetic pathways will find their way to the clinical.