Monoclonal antibodies and small molecule inhibitors are the frontline therapies for patients with solid tumors. However, resistance to treatment and the “undruggability” of multiple key oncogenic proteins emerged as the main limitations.

Targeted protein degraders are recognized as a valuable approach to overcoming these issues. Proteolysis-targeting chimeras (PROTACs) can degrade a protein of interest (POI) and exploit the intracellular ubiquitin-proteasome system (UPS) by targeting the POI to an E3 ubiquitin ligase for ubiquitination and subsequent degradation by proteasomes.

Lv and coworkers reported a first-in-class BCL-xL/2 dual degrader with significantly improved antitumor activity against BCL-xL/2-dependent leukemia cells. BCL-xL and BCL-2 are an anti-apoptotic BCL-2 family which play an important role in regulating tumor cell death, chemoresistance and progression. Inhibition of these BCL-2 family proteins with small molecule inhibitors has been widely studied as a therapeutic strategy for cancers, leading to several anticancer drug candidates (e.g., ABT263).

The structural similarity of both proteins, as well as the differential lysine distribution on their surfaces, make BCL-xL/2 an ideal model system to study how the accessibility of lysines to the E2 component of the ubiquitination complex influences the degradation of a POI by PROTACs. Through computational modelling of the entire NEDD8-VHL Cullin RING E3 ubiquitin ligase (CRLVHL)/PROTAC/BCLxL/ UbcH5B(E2)-Ub/RBX1 complex, Lv et al. showed that the resulting complex can only ubiquitinate the lysines in a defined band region on BCL-xL. By employing this strategy, a series of BCL-xL PROTACs with different linker lengths using a known VHL ligand (BCL-xL ligands – Linker (n = -(CH₂)_x-) - VHL  ligand) were synthesized. In this study, they demonstrated the crucial role of the linker in ternary complex formation induced by the PROTACS and molecule efficiency to degrade its target. The linker of choice, due to it high degree of degradation for both BCL-xL/2, was determined to be n = (CH₂)₆.

Interestingly, the R-epimer on the BCL-xL PROTAC displayed improved potency (DC50 = 6 nM and 48 nM for BCL-xL and BCL-2, respectively) compared with the racemate PROTAC, while the S-epimer was much less potent in degrading BCL-xL and did not degrade BCL-2 at all.

With this finding, the authors provided experimental evidence that the accessibility of lysines on a target protein plays a crucial role in determining the selectivity and potency of a PROTAC in inducing protein degradation. This learning should be an important parameter to guide the future development of PROTACs.

Lv, D., Pal, P., Liu, X. et al. Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity, Nat Commun 12, 6896 (2021). https://doi.org/10.1038/s41467-021-27210-x.

“The EFMC mentoring programme helped me to refine my career plans and to dive into the world of the pharmaceutical industry. I built a relationship with my mentor that will last beyond the mentoring programme, and I was able to get tremendous insights into relevant soft skills and train for future interviews and positions.”

Owing to this program, I benefited from the expertise and the advice of someone who was ready to spend a lot of time for answering my queries, dispelling my doubts, for example. It really was an invaluable opportunity, and I am truly happy to have had this chance.

The Mentoring Programme was a wonderful experience. I had the opportunity to be paired with an expert in the field that could guide me during the first year of my postdoc. He could always answer my doubts about a career in Academia and supervise the steps I accomplished during my career development this year. During this year, which I consider one of the most delicate for the PhD-postdoc transition, I felt that I could count on an external voice that would increase the success rate of my career choices and give me the confidence to keep up with the work.

Interested in becoming a mentor? Reach out to us at administration@efmc.info.

Despite the challenges of 2020/2021 the Basel Chemical Society has delivered an innovative new seminar series that combines industrial and academic speakers in a single virtual or mixed-mode seminar. The format begins with an opening short presentation from an industrial speaker on a successful academic/industrial collaboration within their organization, followed by a traditional lecture by an academic visitor.

These lectures have been broadcast globally and are freely available on the Basel Chemical Society website (https://www.bcg-bcs.ch/).

Although the medicinal chemistry and academic community in Basel is very large, the network has previously been fragmented as it lacked a platform upon which scientists from all walks could congregate. Through the work of the Basel Chemical Society, under the auspices of its current president Karl Heinz Krawinkler, the Basel community has a forum to share expertise and knowledge.

A recent direction of the board is to better connect the tri-nation Basel region both locally and globally. Hence the globally available seminar program and its highly regarded annual symposium which, this year, will focus on integrating the expanding community of biotech start-ups in the region.

The symposium will take place on 20 Jan 2022 and will cover the “Science of Basel Startup Companies”. This is planned as an in-person event that is free to attend after registration.

The prize-winner will attend the XXVII EFMC International Symposium on Medicinal Chemistry (EFMC-ISMC 2022) and EFMC Young Medicinal Chemists’ Symposium (EFMC-YMCS 2022), scheduled to take place in Nice, France on September 4-8 and 8-9, 2022.

Applications and regulations can be found on https://www.efmc.info/ysn-phd-prize

Deadline for submission: January 31, 2022 

How did you get interested in Medicinal Chemistry?

I got interested in Organic Chemistry and Medicinal Chemistry when I was an undergraduate at the pharmacy program especially the reactions and mechanisms of organic compounds. After graduation, I studied a master degree in Organic Chemistry to be the first pharmacist at my school that joins the Department of Chemistry. It was enjoyable to study Organic Chemistry more in depth and to work on the synthesis of organic compounds. I had classes about the chemistry of synthetic and natural compounds. 

Later, during my PhD in Medicinal Biochemistry, I became more interested in these majors due to my great supervisor and the enjoyable challenging research I was working on. This journey led me to become a passionate chemist that transfer her research skills into the synthesis of new medicinal agents. Moreover, to transfer her teaching skills into teaching Organic and Medicinal Chemistry with new methodologies.

Where and when did you obtain your PhD diploma?

I completed my PhD studies in Medicinal Biochemistry; 2016 at the University of North Carolina at Greensboro (UNCG) under supervision of Dr. Mitchell Croatt.

What was the topic of your PhD project?

I was working on two projects: 

• The first one was a Medicinal Chemistry research working on the “synthesis and biological evaluation of neuroprotective agents against stroke derived from isocarbacyclin”.
• The second project was an Organic Chemistry research working on “a novel type of decarboxylation reaction”.

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

I am currently an assistant professor at the Department of Medicinal Chemistry and Phytochemistry - Faculty of Pharmacy in Yarmouk University in Jordan.

What are your current research interests?

My interests are mainly Organic Chemistry and Medicinal Chemistry. In particular, I am working on the preparation and biological evaluation of platinum-complexes anticancer agents. Besides, I have been working on studying teaching methodologies linking Organic Chemistry/Medicinal Chemistry and Clinical Therapeutics courses.

What do you like best about your work?

For teaching, I like teaching Organic Chemistry the most, especially teaching students the way of drawing organic structures and mechanisms. Moreover, I love it when students practice linking the functional groups of the molecule to its physicochemical properties.

For research, I really like working with my lab team in order to solve problems in synthesis. We enjoy the challenge of getting a synthetic step done after searching in literature, many discussions, and trying different conditions. 

What kind of skills does your work require?

Knowledge, communication, leadership, and creativity skills. I remember in a leadership skills workshop I joined at UNCG. The trainer said, “leadership and communication skills are important for an academic position”, which is totally right. As a professor you need to be able to communicate effectively with your students and research team.

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

Bioorganic & Medicinal Chemistry 2019, 27, 338-342.

This paper is the most representative paper of my PhD work. We have been proud to report the shortest synthesis for isocarbacyclin, a neuroprotective agent for ischemic stroke. Great chemistry, step-economical synthesis and new analogues of this medicinal agent.

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

Reading the literature and being patient are the two main ways to success in research, that is why it is called “Chem-is-try”! Reading the literature, working in lab, fail, then try, then keep trying till having the confidence and be expert in your field. I remember spending a year on only one synthetic step to get it work after that. 

Another main thing is never work on only one project. Different type of syntheses will first increase your possibility to get more successful results and second give you the experience to think in different ways and design your own novel ideas.

How would you describe yourself as a supervisor?

I would like to think my team members find me to be the person who motivates them. I try to guide them to work, search, and think independently and at the same time give them freedom in doing research. I enjoy it when later I see how they can search and think by their own, and so create good researchers.

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

When I was a PhD student at UNCG, I was repeating a reaction that I had done several times and worked but with a new bottle of one of the reagents it did not work. This is what I thought at the beginning! I used to get color change in the reaction mixture, but with the new bottle I don’t so I was throwing the whole mixture thinking that it failed. After that a postdoc in the lab ran the reaction with me and said: let’s run NMR for it! But I said: no, the color of the mixture is not changing. He said: even though. And it worked! Later we found that the new reagent bottle did not contain one of the preservatives that caused the color change. It was really embarrassing but I have learned not to judge till making analysis.

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

I recommend “Foye’s Principles of Medicinal Chemistry” for teaching, it is a comprehensive amazing textbook that links Medicinal Chemistry to the drugs’ pharmacology. I also enjoy reading the book “Molecules That Changed the World”; I always have it in my office thinking how great are the researchers who discovered these molecules. It motivates me to work harder. 

I like the website “SciFinder” and use it frequently; I find it the best to look for procedures or novel molecules or anything related to structures.

What would you like to ask from other medicinal chemists?

The Medicinal Chemistry field is a field of innovations and challenges, so I would like to ask my colleges to not to make the same type of compounds over and over. And if you are in academia try to be connected to industry and vice versa.

How did you get interested in Medicinal Chemistry?

During my Bachelors, I became fascinated by the way in which molecules interact and how humans, using rational design, can purposely modulate their behaviour.

Where and when did you obtain your PhD diploma?

I did my PhD in the lab of Prof. Dr. Stefan Günther (Freiburg, Germany). I obtained my diploma in 2014.

What was the topic of your PhD project?

The research in my PhD focused on implementing and applying computational methods for the identification and characterisation of small molecules modulating protein–protein interactions, in particular bromodomains. As part of my PhD, I deepened my knowledge in virtual screening, cheminformatics, and structure-based drug design among others.

Where did you have your postdoc position?

I did my postdoc in the lab of Prof. Dr. Alessio Ciulli (Scotland), working on PROTACs and targeted protein degradation. I implemented and applied molecular dynamics and structure-based drug approaches to study and modulate the mode of action of small-molecule degraders.

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

Since mid-2018 I work as a scientist in computational drug design at Roche (Switzerland). I support portfolio projects especially in pre-clinical stage, i.e. from early target assessment up to lead optimisation, covering diverse therapeutic areas.

What are your current research interests?

I am particularly interested in new therapeutic modalities that challenge undruggability, for example in the fields of targeted protein degradation, RNA-targeting, or protein–protein interaction modulators, and in investigating how computational methods such as machine learning, artificial intelligence, and molecular dynamics, can facilitate that.

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

I work in the early stages of drug development designing molecules with the help of computers. Hopefully, some of those molecules follow their path to clinical trials and, eventually, cure diseases.

What do you like best about your work?

The possibility to work with highly knowledgeable scientists and the constant challenge of innovating new medicines.

What kind of tasks does your work involve?

I use all sorts of computational methods with two goals: first, to study how proteins and small molecules interact and behave, and second, to identify and design new molecules with desired biological activities and appropriate physicochemical properties. For these tasks, I use machine learning, artificial intelligence, molecular dynamics, quantum chemistry, virtual screening, cheminformatics, Free-Wilson analysis, etc.

What kind of skills does your work require?

I believe a computational chemist can benefit the most from combining a wide range of technical and behavioural skills, including programming; a sound understanding of quantum mechanics and non-covalent interactions; machine learning methods, and capabilities for spatial vision and chemical pattern recognition, along with perseverance, curiosity, and a good amount of creativity.

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

I would say that important features include not being afraid of failure, not getting obsessed with success, not avoiding challenges, and being always open to connecting with other scientists and learning new complementary skills.

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

I very strongly recommend Derek Lowe’s blog “In the pipeline”, in which he writes mostly about medicinal chemistry topics (https://www.science.org/blogs/pipeline). I also keep myself up to date about the biotech world and the pharmaceutical industry by checking regularly Fierce Pharma (https://www.fiercepharma.com/).

Which scientist do you admire the most and why?

I admire scientists with the ability to communicate science to non-specialised audiences in an accurate yet appealing manner.

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

I think that in the next few years we will see drugs in the marked that exploit the targeted protein degradation concept, such as PROTACs and molecular glues, to treat diseases.

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

I expect a revolution in medicinal chemistry by further exploiting artificial intelligence, machine learning, and predictive structure-based drug design approaches.

Zachary Armstrong joined the division of Bio-organic Synthesis of the Leiden Institute of Chemistry as Assistant Professor. His group brings in expertise in structural biology, chemoenzymatic synthesis and activity-based probe development. His group is primarily focused on the discovery of inhibitors for enzymes that modify carbohydrates. These enzymes span the tree of life and are fundamental to processes such as viral invasion, cell-to-cell signaling and cancer progression. He has recently employed activity based probes to monitor both human and fungal carbohydrate processing enzymes (doi.org/10.1021/jacs.0c03880, doi.org/10.1021/jacs.0c13059) and determined structures of new carbohydrate processing enzyme families (doi.org/10.1074/jbc.RA119.011591).

Steffen Brünle investigates the structural details of G-protein coupled receptors (GPCRs) (doi.org/10.1016/j.cell.2019.07.028) and recently joined the Biophysical Structural Chemistry department within the LIC as an Assistant Professor. He is particularly interested in allosteric modulation and biased signaling of GPCRs, as well as drug discovery. To unravel the structural underlyings he uses single-particle cryo-electron microscopy (doi.org/10.1073/pnas.1913031116), as well as classical X-ray crystallography, but also time-resolved X-ray crystallography at synchrotrons and free-electron lasers (doi.org/10.1038/s41586-020-2307-8) to unravel the structural dynamics of proteins using photoswitchable compounds.

Sebastian Geibel will join the division of Biophysical Structural Chemistry at the LIC as Associate Professor in January 2022. His lab combines structural (X-ray crystallography, cryo-electron microscopy) with biochemical and microbiological methods to understand transport processes across the bacterial cell envelope such as nutrient uptake or the secretion of virulence factors. A focus is the host pathogen communication in tuberculosis-causing mycobacteria. Recent research highlights are the elucidation of the type VII secretion system (T7SS)  architecture in the mycobacterial cell envelope (doi.org/10.1038/s41586-019-1633-1) and the discovery that the T7SS from Staphylococcus aureus assembles a structure acting as a molecular knife to kill bacterial competitors (doi.org/10.21203/rs.3.rs-95626/v2)

Stephan Hacker joined the Department of Molecular Physiology of the LIC as an Assistant Professor. His group brings in expertise in studying the target proteins of covalent inhibitors proteome-wide with resolution of the addressed binding pocket using mass spectrometry. His group is primarily focused on applications of this technology to identify new druggable targets for antibiotics. They have recently introduced a tailored method for this technology in bacteria (doi.org/10.1002/anie.201912075) as well as new chemical probes that allow studying diverse amino acids (doi.org/10.1021/acscentsci.9b01268, doi.org/10.26434/chemrxiv.14186561.v1).

Anthe Janssen is part of the Department of Molecular Physiology as an Assistant Professor. His research focusses on the development and application of computational and machine learning approaches in early drug discovery programs. He is particularly interested in using machine learning approaches to enhance use of 3D models of proteins (experimental or Alphafolded) for docking and molecular dynamics in the search for kinase or phosphatase inhibitors as cancer treatments (doi.org/10.1021/acs.jcim.8b00640).

Sebastian Pomplun started as a tenure track Assistant Professor at the division of drug discovery and safety within the LACDR in September 2021. His lab (https://pomplunlab.com/) develops technologies for the discovery of novel chemical modalities that can address challenging drug targets. Towards this goal, the group creates innovative drug discovery platforms based on rational design and on combinatorial chemistry to ultimately identify hit compounds targeting therapeutically relevant biomolecules, such as transcription factors (doi.org/10.1021/acscentsci.1c00663; doi.org/10.1021/jacs.1c05666) or nucleic acids involved in cancer (doi.org/10.1002/anie.202003478).

Anne Wentink will start at the Department of Macromolecular Biochemistry of the LIC as Assistant Professor in January 2022. Her lab combines synthetic and structural biology approaches to develop biomimetic molecules inspired by molecular chaperones for research and therapeutic applications. A particular focus is on replicating the recently described ability of the HSP70 chaperone to disaggregate amyloid fibrils associated with neurodegeneration (doi.org/10.1038/s41586-020-2904-6, doi.org/10.1038/s41586-020-2906-4).

5^th RSC / DMDG / DMG New Perspectives in DMPK   

22^nd and 23^rd February 2022, Liverpool, UK

The call for poster abstracts will close on 13th January 2022

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

Synopsis:    Members from across the DMPK research community are encouraged to join colleagues from across academic, industrial, and third-sector institutions and contribute to the ongoing discussion, evolution and application of DMPK in various scenarios.

Fragments VIII:  8^th RSC-BMCS Fragment-based Drug Discovery meeting

27^thand 28^th March 2022, Churchill College, Cambridge

Registration is now open

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

Synopsis:  The aim of the meeting is to continue the focus on case studies in Fragment-based Drug Discovery that have delivered compounds to late-stage medicinal chemistry, preclinical or clinical programmes. Over three-quarters of the presentations will be focused on case studies.

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

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

The call for oral abstracts will close on Monday 31st January 2022

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.