Activities of the Chemical Biology Initiative:

• DESCRIBE CHEMICAL BIOLOGY WITHIN EFMC

The Chemical Biology Initiative members are working towards a better description and understanding of the chemical biology field. Chemical Biology is a truly interdisciplinary area involving the use of chemicals to explore and modulate biological functions at the molecular level. Chemicals involved in these studies allow the study of chemical reactions that are involved in biological processes. The overarching aim of chemical biology is to design, engineer and refine chemicals and/or biological systems to study chemical and biological complexity in a precise and controlled way. The synergistic value of joining different disciplines in the field of chemical biology hampers its precise definition and, not surprisingly, many scientists working in the field do not even define themselves as chemical biologists. EFMC would thus like to highlight its will to include and represent all fields of chemical biology.

For further details, please access the Chemical Biology Initiative webpage on https://www.efmc.info/chemical-biology-initiative.

• ORGANIZATION OF AN E-SYMPOSIUM IN COLLABORATION WITH CHEMISTRY EUROPE

EFMC Chemical Biology Initiative is organizing an e-symposium in collaboration with ChemBioChem (Chemistry Europe) on October 19 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

ChemBioChem and its Editor-in-chief Ruben Ragg regularly organize virtual symposia with a 2-hour format including three presentations from 3 pm to 5 pm (CEST) - save the date for this collaborative event! The website and registration link will be available soon.

• MORE CHEMICAL BIOLOGY IN MEDCHEMBIOWATCH

As the name changes to MedChemBioWatch to reflect the evolution and inclusiveness of EFMC activities, the Chemical Biology Initiative members will actively participate in disseminating relevant information, keeping the community updated with literature highlights, presentations of institutes and teams, as well as reminders about chemical biology activities, events and awards.

The aim of the Chemical Biology Initiative is to actively participate in chemical biology activities of EFMC with an inclusive and open mindset in order to help the Federation both by representing the chemical biology community and by supporting the researchers in the chemical biology field across Europe.

Dr Maria Duca, Chair of the Chemical Biology Initiative

Exportin-1 (XPO1 or CRM1) is a protein transporter involved in shuttling large macromolecules between the nucleus and cytoplasm. XPO1 is responsible for the nuclear export of over 200 different proteins, including the majority of tumor suppressor proteins (TSPs). XPO1 is frequently overexpressed in cancers, leading to the enhanced nuclear export of TSPs. Therefore, XPO1 inhibition is an attractive therapeutic approach for cancer treatment. Selinexor (KPT-330) received FDA approval for multiple myeloma treatment in combination with dexamethasone. It is a first-in-class, orally bioavailable, covalent Exportin-1 inhibitor that specifically binds to the Cys-528 present in XPO1. Additional XPO1 covalent inhibitors are currently in clinical trials for various diseases. The Cravatt group previously demonstrated binding of ligands to Cys528 by fragment electrophiles, showing structural similarities to selinexor and eltanexor. Covalent inhibitors offer the potential of prolonged target engagement, resulting from a dissociation of drug pharmacodynamics (PD) from pharmacokinetics (PK). However, promiscuous electrophiles could potentially cause toxicity issues. Chemical probes of covalent inhibitors enable selectivity profiling and target engagement studies using both in-gel fluorescence and mass spectrometry readouts. Martin et al. developed alkyne-modified clickable probes based on the XPO1 inhibitors selinexor and eltanexor for the labeling of XPO1 in live cells aiming to assess target engagement and proteome-wide selectivity. Two cancer cell lines were selected: (i) KMS11, a human patient derived multiple myeloma cell line, and (ii) SH-SY5Y, a human neuroblastoma. An efficient cellular labeling of XPO1 was demonstrated for the novel clickable probes. The authors used additional technologies, such as thermal profiling methods and reactive cysteine chemoproteomic profiling, to confirm target engagement in living cells in an orthogonal manner. These probes and the reported isothermal dose response (ITDR) XPO1 assay therefore provide a further method for interrogating target occupancy. These results will contribute to a better understanding of the biology of XPO1 inhibitors and consequent efficacy in relevant cellular and in vivo model systems.

Chemoproteomic Profiling of Covalent XPO1 Inhibitors to Assess Target Engagement and Selectivity. Martin JG, Ward JA, Feyertag F, Zhang L, Couvertier S, Guckian K, Huber KVM, Johnson DS. Chembiochem. 2021 Apr 22. doi: 10.1002/cbic.202100038. Online ahead of print. PMID: 33887086

The prize will consist of a diploma, a 500€ grant and a free registration to attend an EFMC Symposium. Due to the current pandemic, the 2021 prize will be conferred at the occasion of the XXVII EFMC International Symposium on Medicinal Chemistry (EFMC-ISMC 2022) and EFMC Young Medicinal Chemists' Symposium (EFMC-YMCS 2022) which will take place in Nice, France on September 4-8 & 8-9, 2022.

How did you get interested in Medicinal Chemistry?

I came first into contact with molecules that interfere with a biological system during a Biology lesson at school. Then we were tasked to write an assay-like text about antibiotics. A glimpse into lexica showed fascinating molecules and fascinating modes of action. This fascination never died, but shifted over the years to the question how to find such molecules in the first place.

Where and when did you obtain your PhD diploma?

I obtained my PhD in the group of Prof. Christa Müller (University of Bonn) in 2007. The topic of my PhD project was the design and synthesis of nucleotide mimetics as ectonucleotidase inhibitors.

Where did you have your postdoc positions?

In the groups of Prof. Christa Müller (University of Bonn) and Prof. Jonathan Hall (ETH Zürich)

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

I am currently a research group leader at TU Dortmund University.

What are your current research interests?

My group is working on the technology of DNA-encoded screening libraries. Basically, we are wondering how to populate the chemical space of these libraries. Is there something like an ideal screening library? In the light of the theoretically synthesizable chemical space, design of screening libraries is a daunting and intellectually stimulating task. Yet, finding novel biologically active chemical matter on a challenging target is so highly rewarding. 

What do you like best about your work?

The freedom to pick a scientific problem and the freedom to walk new ways to work on this problem. A fantastic aspect of a small molecule screening platform technology is that you can venture into many (though certainly not all!) biological targets.  

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

There is not the one greatest achievement, but rather a gradual learning process how to combine best the different scientific disciplines required for library design, screening, and then the follow-up once a molecule has been identified.

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

Difficult to answer, but I would say they fall into the category of “first-time disclosures”, and they raise a lot of questions that need to be answered in further studies. I would pick the identification of a microRNA-lnc-RNA interaction by a chemical biology strategy (Nat Chem Biol, 2015), the demonstration that a certain DNA design enables a broad chemistry scope on oligonucleotide conjugated starting materials (Chem Sci, 2017), the observation that micelle-promoted catalysts enable on-DNA reactions (J Am Chem Soc, 2019), and the identification of TEAD-YAP inhibitors from a small, designed DEL (ACIE, 2020).

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

Curiosity and passion, and a lot of discipline and affinity for the written word.

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

Nothing to report here. I am sorry. DNA and RNA do not explode, they die a silent death.

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

I enjoy reading the blog “In the pipeline” by Derek Lowe. A must-read is the book “In search of the magic bullet”.

Which scientist do you admire the most and why?

I would rather say that I am fascinated by the early era of drug research. How was it possible at all to venture into trying to cure disease with so little knowledge about physiology and toxicology, and they did not even have an NMR machine to fully and timely understand what they were making. Did nobody tell these researchers that drug research is impossible under these circumstances?

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

I do not know whether it is the “most” promising field, but in my opinion the modulation of intracellular protein-protein interactions holds much promise, and with technologies that enable handling unprecedented chemical space - be it virtual or real - I hope we will witness more breakthrough stories in this field.

What would you like to ask from other medicinal chemists?

Don´t underestimate the impact of technologies but readily embrace them, and the value of innovative chemistry for compound design.

In living cells, protein kinases are organized in large signalling complexes comprising adapter proteins, diverse enzymes and regulatory proteins. In recent years it has become increasingly evident, that protein kinases act not only as independent enzymes but that they also function as protein interaction scaffolds organizing the assembly of signalling complexes in a conformation sensitive way. This complexity is also reflected by the response of kinases to inhibitors that may stabilize diverse conformations acting as inhibitors of enzymatic activity only, as modulators of kinase scaffolding roles or both. In this talk, I will exemplify the implications of altering protein interactions by allosteric small molecules as well as canonical ATP competitive inhibitors using a number of selective inhibitors that we developed recently. I will demonstrate how different binding modes that alter protein conformation and dynamics in a distinct way may result in diverse signalling outcomes and phenotypic responses. The important scaffolding roles of protein kinases will also enable targeting new and so far poorly explored members of the kinase family such as catalytically inactive pseudokinases, that represent a considerable number of largely unexplored kinase targets which have been linked to the development of many diseases. 

Register for free here: https://zoom.us/webinar/register/WN_yu2KK3jSTKyutusYrGz2Ug

#GDCh (MedChem Division), #NextGenMedChem.

The jury consisted of Dr. Anna Junker (Westfälische Wilhelms-Universität Münster), Dr. Uwe Grether (Roche), Prof. Dr. Laura Heitman (Leiden University) and Dr. Koen Hekking (Symeres). The prize - € 1000 (sponsored by Symeres), a sculpture and a certificate - was virtually handed over during a webinar of Prof. Dr Luc Brunsveld (TU Eindhoven) about “Stabilization of Protein-Protein Interactions”.

Natalia Ortiz Zacarías will present the winning work as representative of The Netherlands at the 8^th EFMC Young Medicinal Chemist Symposium (EFMC-YMCS) September 9-10, 2021 (virtual event).

The winner Natalia Ortiz Zacarías with Laura Heitman (left)

VIRTUAL - 6^th RSC-BMCS symposium on mastering medicinal chemistry  

29^th and 30^th June 2021 (two afternoon sessions)

Website:   https://www.rsc.org/events/detail/41144/the-bmcs-mastering-medchem-vi

Synopsis:  An ongoing series of conferences intended to provide expert advice and guidance to new practitioners in the field of drug discovery

VIRTUAL - 21^st RSC / SCI Medicinal Chemistry Symposium

12^th to 15^th September 2021, Churchill College, Cambridge, UK

Website:  http://www.rsc.org/events/detail/42821/21st-rsc-sci-medicinal-chemistry-symposium

Synopsis:  One of Europe’s premier biennial Medicinal Chemistry event, focusing on first disclosures and new strategies in medicinal chemistry

VIRTUAL - 4^th Artificial Intelligence in Chemistry - NEW!

27^th-28^th September 2021

The call for abstracts will close on 11^th June (oral) and 13^th August (poster)

Website:  https://www.rsc.org/events/detail/47209/4th-rsc-bmcs-rsc-cicag-artificial-intelligence-in-chemistry

Synopsis:  Artificial Intelligence is presently experiencing a renaissance in the development of new methods and practical applications to ongoing challenges in Chemistry.  The meeting will combine aspects of artificial intelligence and deep machine learning methods to applications in chemistry