16th EFMC Short Course in Medicinal Chemistry

• Doroteja NOVAK, University of Ljubljana, Slovenia

XXVII EFMC International Symposium on Medicinal Chemistry (EFMC-ISMC 2022) & 9th EFMC Young Medicinal Chemists’ Symposium (EFMC-YMCS 2022)

• Gilles DEGOTTE, University of Liège, Belgium
• Elisabetta DI BELLO, Sapienza University of Rome, Italy
• Mihajlo GAJIC, Heinrich Heine Universität Düsseldorf, Germany
• Jessica GRAHAM, Newcastle University, United Kingdom
• Amalia KALAMPALIKI, National and Kapodistrian University of Athens, Greece
• Elizabeth A. LOPES, University of Lisbon, Portugal
• Carlos MAGALHAES DA SILVA, University of Aveiro, Portugal
• Maria MANEIRO REY, University of Santiago de Compostela, Spain
• Ángela MARTÍN-SERRANO ORTIZ, University of Alcalá, Spain
• Ana Teresa SILVA, University of Porto, Portugal

Activities of the Chemical Biology Initiative

THE CHEMICAL BIOLOGY-MEDICINAL CHEMISTRY CONTINUUM: EFMC’s VISION

The Chemical Biology Initiative members worked on a description of EFMC’s current understanding of chemical biology and its relation to interfacing disciplines such as medicinal chemistry, biology and biochemistry. In the editorial that the working group members published last year in ChemBioChem journal, the authors described chemical biology and medicinal chemistry as part of a scientific continuum, chemical biology being interdisciplinary and involving the development and use of chemical tools to explore and modulate biological systems in a precise and controlled approach.

You can read the articles following this link: https://chemistry-europe.onlinelibrary.wiley.com/doi/full/10.1002/cbic.202100319

ORGANIZATION OF AN E-SYMPOSIUM IN COLLABORATION WITH CHEMISTRY EUROPE

EFMC Chemical Biology Initiative organized an e-symposium in collaboration with ChemBioChem (Chemistry Europe) on October 19, 2021 in the presence of three outstanding speakers:

• Ed Tate, Imperial College London, UK
• Sascha Hoogendoorn, University of Geneva, Switzerland
• Thomas Carell, Ludwig-Maximilians-Universität München, Germany

Can you tell us more about your background?

I received my PhD diploma in chemistry (cum laude) from Utrecht University on April 2002. My thesis was about the metabolism and neuroprotective properties of anandamide, an endogenous ligand of the cannabinoid receptors. After a post-doctoral position in cell biology in the lab of Prof. dr. Vincenzo di Marzo, I worked for almost eight years in the Research Laboratories of Merck (former Organon) in the Netherlands. I was a group leader in the medicinal chemistry department of Prof. dr. Stan van Boeckel and served as project leader for several programs ranging from hit identification up to clinical candidate selection. In 2012, I decided to go back to academia to start my own research group, where I combine medicinal chemistry with chemical biology at Leiden University.  

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

Currently, I am a full professor and chair of Molecular Physiology at the Leiden Institute of Chemistry and a principal investigator of Oncode Institute. Our aim is to design, synthesize and apply chemical tools to study important biological and biomedical questions. We have a focus on kinase and lipid signalling. We use techniques from different fields, including chemical biology, computational chemistry, medicinal chemistry and molecular biology, to determine and predict the interaction of small molecules with proteins in physiological and disease processes.

Our long-term aim is to discover drug candidates to treat cancer, (drug-resistant) infections and brain disorders. The group consists of two assistant professors (Dr. Stephan Hacker and Dr. Anthe Janssen), 4 post-docs, 16 PhD-students & technicians and >20 M.Sc and B.Sc students. We are embedded in the Leiden Early Drug Discovery network (https://www.universiteitleiden.nl/en/science/led3). Finally, I am the workstream leader of small molecule drug discovery from Oncode-PACT, an (inter)national consortium that has recently been awarded 325 million Euros from the Netherlands government to accelerate preclinical drug discovery for oncology (https://www.oncode.nl/Oncode-PACT).

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

The integration of activity-based protein profiling (ABPP, chemical proteomics) in the drug discovery process has allowed us to discover and profile inhibitors of lipid and kinase signalling. For example, we have shown that BIA 10-2474, a FAAH inhibitor which killed a healthy volunteer in a phase 1 clinical trial in France in 2016, was a promiscuous lipase inhibitor that disrupted the lipid homeostasis in human cortical neurons (1). These results were used in the decision-making process by companies to resume clinical trials with other FAAH inhibitors.

Currently, we collaborate with biotech and pharmaceutical companies to apply ABPP in the hit- and lead optimisation process to guide the selection of the best clinical candidates. ABPP has also enabled us to discover the first brain active inhibitors of various biosynthetic enzymes of distinct endocannabinoids (2,3). These compounds are now widely used to study the physiological role of these signalling lipids. Furthermore, we developed a target validation strategy for kinases in which we combine ABPP with chemical genetics (4).

I am still amazed that by changing one amino acid in an endogenously expressed kinase in human cells by CRISPR-Cas9, we could visualize target engagement of this specific kinase by a complementary, fluorescently labelled covalent probe.

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

1. Van Esbroeck et al., Science, 2017, 356, 1084
   https://www.science.org/doi/abs/10.1126/science.aaf7497 
2. Ogasawara et al., Proc. Natl. Acad Sci. USA, 2016, 113, 26
   https://www.pnas.org/doi/abs/10.1073/pnas.1522364112
3. Mock et al., Nature Chem. Biol., 2020,16, 667
   https://www.nature.com/articles/s41589-020-0528-7
4. Van der Wel et al., Nature Comm., 2020, 11, 1 
   https://www.nature.com/articles/s41467-020-17027-5

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

To have a successful PhD, it is important that you are intrinsically motivated and are curious to learn new topics and techniques. Read the literature, go to conferences and talk to people. You are venturing into new, unknown territory; therefore, it is important to be perseverant, not to give up when something is not working the first, second or even a third time. If it was easy, then somebody else would already have done it.

I like to work on the interface between chemistry and biology, because I am convinced that new chemical tools and methods will allow us to address important biological questions. In my group chemists and biologists work closely together and they have to learn to speak each other’s language to move their projects forward. Thus, team spirit, collaboration and good communication skills are important as well. If you share success, it will become bigger.  

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

At the first day of my PhD, I made use of a magnetic stirrer to dissolve some components of a buffer. I put the bottle next to a flask of a colleague. I did not know the magnetic stirrer was also a heating block. By turning it on, I accidently denatured her precious protein preparation, which had taken her several weeks to obtain…. that was quite an introduction. Fortunately, we could still get along after this embarrassing mistake.

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

Of course, everyone working in medicinal chemistry should read the blog ‘In the pipeline’ from Derek Lowe. 

Which scientist do you admire the most and why?

Prof. dr. Raphael Mechoulam is an inspiration for me. He discovered the structure of THC, the psychoactive component of cannabis sativa in 1964 and almost 30 years later he also identified anandamide, the first endogenous cannabinoid in the brain. Thereby, he, as a medicinal chemist, discovered a whole new physiological system and started a novel field with great opportunities for drug discovery.

Which field of medicinal chemistry do you consider the most promising for the future?

As a medicinal chemist/chemical biologist, I think it is important to develop technologies that will allow us to predict and characterize the interaction of small molecules across the entire human proteome in a living cell. Computational chemical biology (such as machine learning) combined with chemical proteomics, metabolomics and molecular & structural biology will allow us to make a molecular encyclopaedia of ligand-protein interactions and their function. Single molecule resolution imaging techniques using specific fluorescent probes will allow us to localize where these interactions take place in cells or tissues. Together, this will provide a better molecular understanding of human biology in health and disease and will lead to more efficacious and safer drugs in an efficient manner.

Swiss Summer Schools are out-of-town seminars intended for MSc, PhD students and postdoctoral researchers with a focus on chemical synthesis or chemical biology. They offer a platform for the scientific exchange with peers and lecturers from academia and industry. The goal is that the young researchers actively participate in the scientific exchange and also present a poster or a short communication on their research. The scientific program, which received EFMC certification, will consist of speakers from industry and academia giving courses on different topics in chemical biology, sponsored industry lectures, career sessions and workshops. For more details and registration please check out the website.

Organized by the NCCR Chemical Biology, The International Symposium on Chemical Biology is one of the premier events for local and international communities of researchers interested in all aspects of chemical biology.  Its 4^th edition is taking place on November 8 to 10, 2022 in Geneva, Switzerland and online. The event once again boasts an impressive speaker line-up featuring 15 international leading scientists in the field covering a great diversity of topics. These talks will be set in an overall framework that is carefully crafted to provide ample opportunity for networking across the global community of academics and industrial scientists, as well as to stimulate interdisciplinary discussions. Travel awards dedicated to recognize excellent science from young researchers presenting posters, are also planned.

During the event, the EFMC and the SCS will officially announce that they will take over the organization of the Symposium in the future and provide further information on the 2023 edition in Basel, Switzerland.

Discover the full list of speakers & topics

Important deadlines:

Early bird registration to the in-person event (Geneva): June 30, 2022

Regular registration: October 18, 2022

Author: Antonia F. Stepan, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Ho''.chr('64256').''mann-La Roche AG, 4070 Basel, Switzerland

In 2013, Serafimova assessed a series of electrophilic molecules that  engaged  non-catalytic  cysteines  in  a  covalent  manner, but  with  variable  target  residence  times, driven by the various stabilizing interactions of the molecule in the protein binding site. These reversible covalent inhibitors were shown to rapidly dissociate from common thiols while maintaining sustained inhibition of a target protein even after washout. This technology, therefore, has the potential to allow medicinal chemists to fashion inhibitors with the potential for selectivity gained by inhibiting only  targets  with  a  conserved cysteine, and  minimal  exposure  requirements  inherent  with  covalent  inhibition.  The reversible covalent approach furthermore mitigates  risk  of  irreversible  binding  to  non-target  cysteines  or  endogenous  thiols,  but  also  allows  the  potential  to  improve selectivity among targets sharing a common cysteine.This technology has been used to identify selective inhibitors of kinases such as BTK and FGFR as well as the LMP7 subunit of the immunoproteasome. Based on our interest in BTK inhibition for the treatment of immune-mediated disorders, we embarked on a drug development effort  to  identify  reversible  covalent  inhibitors,  culminating  in  the identification of PRN473 for topical administration and PRN1008 (rilzabrutinib) as an oral BTK inhibitor currently in multiple phase 3 studies.

Register for free here: 
https://us06web.zoom.us/webinar/register/WN_qPK2vk9eSbyf6q8i2z3dLg

#GDCh (MedChem Division), #NextGenMedChem.

AI in Chemistry: 5^th RCS-BMCS /RSC-CICAG Artificial Intelligence in Chemistry

1^st  and 2^nd September 2022, Churchill College, Cambridge and virtual

The call for abstracts will close on 22^nd April, 2022 (oral) and 2^nd June, 2022 (poster)

Website:  https://www.rscbmcs.org/events/ai-in-chemistry-2/

Synopsis:  Artificial Intelligence is presently experiencing a renaissance in development of new methods and practical applications to ongoing challenges in Chemistry. Following the successes of three annual “Artificial Intelligence in Chemistry” meetings starting in 2018, we are pleased to announce that the Biological & Medicinal Chemistry Sector (BMCS) and Chemical Information & Computer Applications Group (CICAG) of the Royal Society of Chemistry are once again organising a conference to present the current efforts in applying these new methods. The meeting will be held over two days and combine aspects of artificial intelligence and deep machine learning methods to applications in chemistry

8^th RSC/SCI symposium on GPCRs in Medicinal Chemistry

5^th to 7^th October 2022, Verona, Italy

Delegate Registration and Exhibitor/Sponsor registration is now open
The call for poster  abstracts will close on Thursday, 11^th August

Closing date for bursary application is Tuesday, 23^rd August

Website:  https://www.rscbmcs.org/events/gpcrs/

Synopsis: The key role of G protein-coupled receptors (GPCRs) in human disease underpins their importance to modern medicine. We are pleased to be holding this 8th meeting in the series on GPCR drug discovery, which will combine cutting edge medicinal chemistry with innovative structural biology and novel drug design approaches.

RSC-BMCS Targeted Protein Degradation: “Three’s a crowd ?”
16^th and 17^th November 2022, Virtual

Abstract submission will be open soon, please keep checking website for updates

Website: https://www.rscbmcs.org/events/protdeg22/

Synopsis: Targeted protein degradation is a rapidly developing field of drug discovery which is expanding the proportion of human proteins which are tractable drug targets. Whereas conventional small molecules are designed to block the activity of a protein, targeted protein degraders act by harnessing biological pathways to remove the protein entirely. This conference will showcase presentations showing the application and development of degradation technologies such as molecular glues and heterobifunctional degraders (e.g. PROTACs)